RESUMO
Background: Mesenchymal Consensus Molecular Subtype 4 (CMS4) colon cancer is associated with poor prognosis and therapy resistance. In this proof-of-concept study, we assessed whether a rationally chosen drug could mitigate the distinguishing molecular features of primary CMS4 colon cancer. Methods: In the ImPACCT trial, informed consent was obtained for molecular subtyping at initial diagnosis of colon cancer using a validated RT-qPCR CMS4-test on three biopsies per tumor (Phase-1, n=69 patients), and for neoadjuvant CMS4-targeting therapy with imatinib (Phase-2, n=5). Pre- and post-treatment tumor biopsies were analyzed by RNA-sequencing and immunohistochemistry. Imatinib-induced gene expression changes were associated with molecular subtypes and survival in an independent cohort of 3232 primary colon cancer. Results: The CMS4-test classified 52/172 biopsies as CMS4 (30%). Five patients consented to imatinib treatment prior to surgery, yielding 15 pre- and 15 post-treatment samples for molecular analysis. Imatinib treatment caused significant suppression of mesenchymal genes and upregulation of genes encoding epithelial junctions. The gene expression changes induced by imatinib were associated with improved survival and a shift from CMS4 to CMS2. Conclusion: Imatinib may have value as a CMS-switching drug in primary colon cancer and induces a gene expression program that is associated with improved survival.
RESUMO
BACKGROUND: Health related quality of life (HRQL) is an important outcome measure in geriatric oncology. Surgery is the main treatment for colorectal cancer (CRC) but has been associated with a loss of HRQL in older patients. This study aimed to identify determinants for a decreased HRQL at three months after CRC diagnosis. METHOD: This multi-centre observational cohort study (NCT04443816) included 273 patients aged ≥70 years diagnosed with non-metastatic CRC. A multi-domain frailty screening was performed in each patient. A decreased HRQL was defined as a mean difference ≥ 10 on the EORTC QLQ-C30 questionnaire between baseline and three months after CRC diagnosis. Determinants of a decreased HRQL were analysed using multivariable logistic regression. RESULTS: A decrease in HRQL occurred in 63 patients (23.1%). Non-surgical patients had the highest risk of decreased HRQL three months after diagnosis (adjusted odds ratio (OR) 6.4 (95% confidence interval (CI) 2.0-19.8)). The Charlson Comorbidity Index (CCI) (aOR 2.3 (95% (CI) 1.2-4.2)), the American Association of Anesthesiologists class (aOR 2.6 (95%CI 1.4-4.9)), impaired daily functioning (aOR 2.7 (95%CI 1.3-5.6)) and dependent living (aOR 1.9 (95%CI 1.1-4.5)) were associated with a decreased HRQL, mainly caused by non-surgical patients. In surgical patients, a major postoperative complication was a strong determinant of decreased HRQL and was associated with preoperative comorbidity and cognitive impairment (aOR 4.0 (95%CI 1.9-8.8)). CONCLUSION: Frailty characteristics are highly prevalent in older patients at time of CRC diagnosis but not strongly associated with a decreased HRQL after three months. Non-surgical patients and patients with major postoperative complications had the highest risk of decreased HRQL. Registered at clinicaltrials.gov trial number: NCT04443816.