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Background: Locally advanced rectal cancers (LARC) are treated with neoadjuvant chemoradiotherapy (nCRT), total mesorectal excision (TME), and adjuvant chemotherapy, and identifying reliable prognostic/predictive biomarkers is currently warranted for LARC. Methods: Comprehensive genomic profiling was performed in 76 LARC patients who received nCRT plus TME. All 76 patients had baseline tissue biopsies, 72 had paired baseline tissue biopsies and surgical tumor samples, and 55 had paired surgical tumor and margin samples. Post-nCRT tumor regression grade (TRG) and post-surgical disease-free survival (DFS) were used to assess treatment outcomes. Results: Baseline KRAS mutation (P=0.022) and MYC amplification (P=0.047) appeared to be independent prognostic factors for nCRT, with KRAS/MYC-mutated patients having higher tumor regression grade (TRG) and lower immune infiltration. Intriguingly, high radiation doses during nCRT were correlated with improved nCRT response in KRAS/MYC-positive patients. Additionally, aberrations in multiple signaling pathways, especially JAK-STAT (P=0.022), were enriched in TRG3 patients after nCRT, implying that they might be resistance mechanisms that impair nCRT efficacy. The post-surgical FBXW7 mutation was significantly associated with shorter disease-free survival (P=0.01), while treatment-induced branched tumor evolutionary pattern and the molecular level of residual tumor at the surgical margin were significantly correlated with both poorer nCRT response and higher post-surgical recurrence risk. Conclusions: Comprehensive genomic profiling helps identify multiple molecular prognostic and/or predictive biomarkers that could predict patients’ clinical outcomes to nCRT and TME and direct nCRT treatment regimen, thus facilitating more accurate prognostic estimation, a better balance between treatment efficacy and quality of life, and timely adjusted treatment decisions. Citation Format: Li Li, Kewen He, Aijie Li, Yang Xu, Jiaohui Pang, Dianbin Mu, Jie Ma, Hong Ge, Aurian Maleki, Xueting Qin, Xian Zhang, Qiuxiang Ou, HaiMeng Tang, Yang Shao, Jinming Yu, Shuanghu Yuan. Genomic features, evolutionary patterns, and minimal residual disease at surgical margins as novel prognostic/predictive biomarkers in locally advanced rectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3309. |
