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However, achieving a complete response (CR) for \u201cwatch-and-wait\u201d strategies is hindered by high response heterogeneity. Although immunotherapy-combined NAT has expanded the candidate pools, the predictive significance of molecular alterations remains unclear.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>This study aimed to evaluate clinical and genomic profiles of rectal cancer patients undergoing NAT to identify response predictors and to develop a nomogram for estimating CR probability.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Design<\/jats:title>\n                    <jats:p>Retrospective, single-center cohort study.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>This study included 437 patients with rectal adenocarcinoma at Fudan University Shanghai Cancer Center between December 2019 and March 2023. Patients underwent paired tumor and germline genomic sequencing (887-gene panel) before NAT. Logistic and Cox regression analyses were performed to identify clinical and genetic risk factors associated with tumor response and long-term survival.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Of the 437 patients, 96.6% had microsatellite-stable (MSS) tumors. In the MSS locally advanced rectal cancer cohort (N = 307), the CR rate was 35.5%. Multivariate analysis identified immunotherapy-combined NAT (iTNT) (OR 4.41, 95% CI: 2.42\u20138.27),\n                      <jats:italic toggle=\"yes\">SYNE1<\/jats:italic>\n                      mutation (OR 2.12, 95% CI: 1.06\u20134.26), negative mesorectal fascia (MRF) status (OR 0.34, 95% CI: 0.17\u20130.66), and lower tumor location (OR 0.48, 95% CI: 0.27\u20130.84) as independent predictors of CR.\n                      <jats:italic toggle=\"yes\">KRAS<\/jats:italic>\n                      mutation was the sole independent predictor of reduced disease-free survival (DFS; HR 1.93, 95% CI: (1.11\u20133.36),\n                      <jats:italic toggle=\"yes\">p<\/jats:italic>\n                      = 0.020).\n                      <jats:italic toggle=\"yes\">KRAS<\/jats:italic>\n                      G12D subtype was associated with the worst 2-year distant metastasis-free survival (71.3%) and exhibited a distinct predilection for lung metastasis. The clinical-genomic nomogram yielded strong discrimination (AUC = 0.705) and calibration, with favorable DCA net benefit.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      Clinical and genomic features jointly determine outcomes in MSS rectal cancer.\n                      <jats:italic toggle=\"yes\">SYNE1<\/jats:italic>\n                      mutation serves as a novel biomarker for CR, while\n                      <jats:italic toggle=\"yes\">KRAS<\/jats:italic>\n                      mutations, especially the G12D subtype, identify patients at high risk for systemic relapse. The clinical-genomic nomogram facilitates individualized selection for organ-preservation strategies.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1177\/17588359261484310","type":"journal-article","created":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T14:29:52Z","timestamp":1788186592000},"update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":0,"title":["Integrating clinical and genomic features to predict response to neoadjuvant therapy in microsatellite-stable rectal cancer"],"prefix":"10.1177","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9435-9799","authenticated-orcid":false,"given":"Lijie","family":"Zhang","sequence":"first","affiliation":[{"name":"Fudan University Shanghai Cancer Center"},{"name":"Shanghai Medical College"},{"name":"Fudan University"},{"name":"Shanghai Clinical Research Center for Radiation Oncology"},{"name":"Shanghai Key Laboratory of 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