Perineural invasion is associated with an aggressive phenotype and reduced in vitro capecitabine sensitivity in colorectal cancer
- 1Affiliated Cancer Hospital, Shanxi Medical University
- 2Fifth Clinical Medical School, Shanxi Medical University
- 3Department of Pathology, Shanxi Province Cancer Hospital/Shanxi Hospital Affiliated to Cancer Hosipital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University
Abstract
Background: Perineural invasion (PNI) is an aggressive biological feature of colorectal cancer (CRC) driven by active crosstalk between tumor cells, Schwann cells, and the neural microenvironment. Although PNI is associated with recurrence, distant metastasis, and chemoresistance, its pathologic diagnosis is constrained by sampling limitations and inter-observer variability, and direct patient-level evidence linking PNI to the cellular sensitivity of specific cytotoxic agents such as capecitabine is lacking.
Methods: We performed a retrospective dual-cohort study of 724 patients with histologically confirmed colorectal adenocarcinoma who underwent R0 resection between January 2024 and August 2025 at a tertiary cancer center in China. Cohort A (n = 430) was used to develop and validate a clinicopathologic nomogram for PNI through LASSO regression, multivariable logistic modeling, bootstrap-corrected internal validation, and internal hold-out validation. Discrimination, calibration, and clinical utility were assessed by area under the receiver operating characteristic curve (AUC), mean absolute error (MAE), Hosmer–Lemeshow test, and decision curve analysis. The association between PNI and distant metastasis was examined in the full cohort by multivariable logistic regression. Cohort B (n = 390) underwent ATP-based in vitro tumor chemosensitivity assays on patient-derived tumor cells; the association between PNI status and capecitabine sensitivity was evaluated by ordinal logistic regression with inverse probability of treatment weighting (IPTW) and propensity score matching (PSM).
Results: The six-factor nomogram (T stage, N stage, lymphovascular invasion, tumor budding, KRAS, Ki-67) achieved AUCs of 0.778, 0.741, and 0.803 in the development subset, internal hold-out validation subset and full cohort, respectively, with MAE of 0.023 and Hosmer–Lemeshow P = 0.56. PNI was independently associated with distant metastasis.Patient-derived tumor cells from PNI-positive tumors exhibited markedly reduced in vitro capecitabine sensitivity, consistent across IPTW (multivariable OR = 0.62, 95% CI 0.44–0.88, P = 0.007) and PSM (multivariable OR = 0.34, 95% CI 0.15–0.77, P = 0.009) analyses.
Conclusions: PNI-positive CRC harbors a reduced in vitro capecitabine sensitivity and an elevated metastatic propensity. The proposed six-factor nomogram offers a practical postoperative tool for PNI risk stratification, while the convergent clinical and in vitro evidence may inform hypothesis-generating individualized strategies pending prospective validation of fluoropyrimidine-based adjuvant therapy in PNI-positive patients.
Related
- P103 A rash decision? A possible capecitabine associated discoid lupus with anti-Ro positivity
- Pdk1-dependent metabolic heterogeneity promotes aggressive colorectal cancer through cell-intrinsic interferon signaling
- Cancer-Associated Fibroblasts in Perineural Invasion: Biological Roles and Therapeutic Strategies
- A regenerative stem cell phenotype marked by ANXA1 defines aggressive colorectal cancer biology
- Spatial epigenomics reveals ancestry-associated regulatory states linked to aggressive prostate cancer biology
BibTeX
@article{yang2026perineural,
title = {{Perineural invasion is associated with an aggressive phenotype and reduced in vitro capecitabine sensitivity in colorectal cancer}},
author = {Shuzhe Yang and Zhongyuan Bai and Yanan Li and Chentong Mao and Taohui Han and Shanna Liang and Yanfeng Xi},
journal = {Frontiers in Oncology},
year = {2026},
month = oct,
doi = {10.3389/fonc.2026.1961159},
url = {https://www.frontiersin.org/articles/10.3389/fonc.2026.1961159/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Perineural invasion is associated with an aggressive phenotype and reduced in vitro capecitabine sensitivity in colorectal cancer
AU - Shuzhe Yang
AU - Zhongyuan Bai
AU - Yanan Li
AU - Chentong Mao
AU - Taohui Han
AU - Shanna Liang
AU - Yanfeng Xi
PY - 2026
DA - 2026/10/21
JO - Frontiers in Oncology
DO - 10.3389/fonc.2026.1961159
UR - https://www.frontiersin.org/articles/10.3389/fonc.2026.1961159/full
AB - Background: Perineural invasion (PNI) is an aggressive biological feature of colorectal cancer (CRC) driven by active crosstalk between tumor cells, Schwann cells, and the neural microenvironment. Although PNI is associated with recurrence, distant metastasis, and chemoresistance, its pathologic diagnosis is constrained by sampling limitations and inter-observer variability, and direct patient-level evidence linking PNI to the cellular sensitivity of specific cytotoxic agents such as capecitabine is lacking. Methods: We performed a retrospective dual-cohort study of 724 patients with histologically confirmed colorectal adenocarcinoma who underwent R0 resection between January 2024 and August 2025 at a tertiary cancer center in China. Cohort A (n = 430) was used to develop and validate a clinicopathologic nomogram for PNI through LASSO regression, multivariable logistic modeling, bootstrap-corrected internal validation, and internal hold-out validation. Discrimination, calibration, and clinical utility were assessed by area under the receiver operating characteristic curve (AUC), mean absolute error (MAE), Hosmer–Lemeshow test, and decision curve analysis. The association between PNI and distant metastasis was examined in the full cohort by multivariable logistic regression. Cohort B (n = 390) underwent ATP-based in vitro tumor chemosensitivity assays on patient-derived tumor cells; the association between PNI status and capecitabine sensitivity was evaluated by ordinal logistic regression with inverse probability of treatment weighting (IPTW) and propensity score matching (PSM). Results: The six-factor nomogram (T stage, N stage, lymphovascular invasion, tumor budding, KRAS, Ki-67) achieved AUCs of 0.778, 0.741, and 0.803 in the development subset, internal hold-out validation subset and full cohort, respectively, with MAE of 0.023 and Hosmer–Lemeshow P = 0.56. PNI was independently associated with distant metastasis.Patient-derived tumor cells from PNI-positive tumors exhibited markedly reduced in vitro capecitabine sensitivity, consistent across IPTW (multivariable OR = 0.62, 95% CI 0.44–0.88, P = 0.007) and PSM (multivariable OR = 0.34, 95% CI 0.15–0.77, P = 0.009) analyses. Conclusions: PNI-positive CRC harbors a reduced in vitro capecitabine sensitivity and an elevated metastatic propensity. The proposed six-factor nomogram offers a practical postoperative tool for PNI risk stratification, while the convergent clinical and in vitro evidence may inform hypothesis-generating individualized strategies pending prospective validation of fluoropyrimidine-based adjuvant therapy in PNI-positive patients.
SN - 2234-943X
ER -