Cancer-associated fibroblast signature and SMAD4 mutation in resistance to adjuvant chemotherapy in stage III colon cancer patients

Introduction Stage III colon cancer (CC) is routinely treated with resection followed by adjuvant chemotherapy (ACT). However, 50 % of patients are cured by surgical intervention alone, whilst another 30 % experience disease recurrence despite ACT. This study aimed to identify biomarkers prognostic of recurrence and/or predictive of response to ACT. Materials and Methods Prognostic value of clinicopathological features, transcriptional profiles and genomic mutations was examined for patients with microsatellite stable (MSS) and instable (MSI) CC receiving ACT, as well as in a sub-cohort of patients with minimal residual disease (MSS-MRD) detected by post-surgery circulating tumour DNA. Results In MSS patients (N = 199), recurrence was associated with pT4 and/or pN2 tumours (HR 3.5 [2.0–5.9], p ' 0.001); CMS4 (HR 2.6 [1.2–5.4], p = 0.008); a high cancer-associated fibroblast (CAF) signature (HR 2.2 [1.4–3.6], p = 0.001); and SMAD4 mutations (HR 2.1 [1.1–4.2], p = 0.027). In the MSS-MRD sub-cohort (N = 23), lack of response to ACT was associated with a high CAF-signature (HR 5.3 [1.7–17], p = 0.002) and SMAD4 mutations (HR 3.4 [0.9–13], p = 0.060). Discussion A high CAF-signature and SMAD4 mutations have prognostic value for recurrence both in MSS CC and in MRD, indicating potential predictive value for response to ACT. This molecular profile provides leads to design novel therapies for patients resistant to standard ACT.