Predicting pathological complete response based on multi-time point ¹⁸ F-FAPI PET/CT in locally advanced rectal cancer.

Abstract

e15649 Background: Accurate prediction of pathological complete response (pCR) following neoadjuvant short-course radiotherapy (SCRT) combined with immunotherapy and chemotherapy in locally advanced rectal cancer (LARC) remains challenging. Methods: This prospective, exploratory single-center study (identifier: NCT06608537) enrolled 49 LARC patients treated with neoadjuvant SCRT plus PD-1 inhibitor and CAPOX. All patients underwent baseline and preoperative 18 F-FDG and 18 F-FAPI PET/CT, with pre-operative 18 F-FAPI PET acquired via a dynamic, multi-time-point protocol (30, 60, 90, 120 min post-injection). Histopathological analysis of baseline biopsies quantified tertiary lymphoid structures (TLS), immune cell densities, cancer-associated fibroblast (CAF) markers, and tumor microenvironment phenotypes. A pCR predictive model was developed by integrating PET semi-quantitative parameters with histopathological features via LASSO regression, followed by multivariable logistic regression. The model’s performance was rigorously assessed using repeated nested cross-validation. Results: The pCR rate was 49.0% (24/49). Multi-time-point 18 FFAPI PET imaging revealed distinct kinetic profiles between responders and non-responders, providing superior predictive value compared to other FAPI or FDG parameters. Histopathologically, the presence of pretreatment intratumoral tertiary lymphoid structures (iTLS) was significantly associated with pCR. An integrative multivariable model, incorporating preoperative 18 F-FAPI TIMR at 30 min post-injection, RI 34 18 F-FAPI TIMR, CD20 + B-cell density and iTLS number, achieved a robust predictive performance with a mean AUC of 0.874 (95% CI: 0.858–0.890). Exploratory mechanistic studies identified CAF-derived TGFβ as a key suppressor of TLS formation, linking stromal biology to treatment response. Conclusions: Integrating preoperative 18 F-FAPI PET with immune-stromal histopathology offers a novel, non-invasive strategy for predicting pCR in LARC. This multimodal approach outperforms anatomic imaging and tumor cell-targeted molecular imaging, providing a clinically translatable framework to personalize treatment selection and support organ-preservation strategies. Clinical trial information: NCT06608537 .