The Role of p53 Expression in Patients with RAS/BRAF Wild-Type Metastatic Colorectal Cancer Receiving Irinotecan and Cetuximab as Later Line Treatment

Abstract

Background Preclinical and clinical data indicate that p53 expression might modulate the activity of the epidermal growth factor receptor (EGFR), influencing response/resistance to anti-EGFR monoclonal antibodies. However, the association between p53 status and clinical outcome has not been clarified yet. Objective In our study, we evaluated the role of p53 expression in patients with RAS/BRAF wild-type metastatic colorectal cancer (mCRC) receiving irinotecan/cetuximab in an exploratory and a validation cohort. Patients and Methods p53 expression was analysed in patients with RAS/BRAF wild-type mCRC receiving second-line or third-line irinotecan/cetuximab. Survival distribution was assessed by the Kaplan-Meier method, while the log-rank test was used for survival comparison. Results Among 120 patients with RAS/BRAF wild-type mCRC included in our analysis, 52 (59%) and 19 (59%) patients showed p53 overexpression in the exploratory and validation cohort, respectively. In the exploratory cohort, low p53 expression was correlated with better median progression-free survival (hazard ratio 0.39; p < 0.0001), median overall survival (hazard ratio: 0.23; p < 0.0001) and response rate (p < 0.0001). These results were confirmed by data of the validation cohort where we observed better median progression-free survival (hazard ratio: 0.48; p = 0.0399), median overall survival (hazard ratio: 0.26; p = 0.0027) and response rate (p =0.0007) in patients with p53 normal expression mCRC. Conclusions In our study, p53 overexpression was associated with anti-EGFR treatment resistance in patients with RAS/ BRAF WT mCRC, as confirmed in a validation cohort. Larger studies are needed to validate the role of p53 and investigate EGFR cross-talk in these patients.Pina Ziranu and Eleonora Lai contributed equally to this work.

Prediction of Response to Anti-Angiogenic Treatment for Advanced Colorectal Cancer Patients: From Biological Factors to Functional Imaging

“…Today, anti-angiogenic treatment represents a cornerstone of mCRC patient management in both the first-and second-line settings [3][4][5][6][7][8][9][10][11][12]. Unfortunately, the real OS gain from bevacizumab, aflibercept, and ramucirumab emerged from clinical trials and reallife data is about 1.4 to 1.6 months, which is quite marginal in the clinical history of a mCRC patient [3][4][5][6][7][8][9][10][11][12]16,17,[116][117][118][119]. The same concept applies even more to the role of regorafenib in further lines of treatment [20,120].…”

“…Nowadays, the standard of care for mCRC treatment is represented by first-line fluoropyrimidine-based chemotherapy, either single agent or in combination with oxaliplatin or irinotecan (doublet or triplet regimen), plus biological agents targeting either vascular endothelial growth factor (VEGF, bevacizumab) or epidermal growth factor receptor (EGFR, panitumumab or cetuximab). The treatment plan is chosen according to the mutational/molecular status of the tumor and the clinical features of the patient [7,8]. Immunotherapy with immune-checkpoint inhibitors (pembrolizumab) is restricted to mCRC patients with mismatch-repair deficiency (dMMR) or high microsatellite instability (MSI-H) [9].…”

Liver endothelium promotes HER3-mediated cell survival in KRAS wild-type and mutant colorectal cancer cells

“…Meanwhile, mutations in other key oncogenic genes also affect cancer cell functions and response to therapies. For example, mutations in PIK3CA and TP53 occur often in CRC and are also suggested to render mCRC resistant to EGFR targeted therapies [47][48][49][50] . Speci cally, PIK3CA mutations lead to activation of PI3K, another key mediator in RTK signaling pathways including HER3 49,51 .…”

Liver Endothelium Promotes HER3-mediated Cell Survival inKRASWild-type and Mutant Colorectal Cancer Cells

“…In addition to KRAS and PIK3CA mutations, CRC cells used in this study harbored mutations in TP53. Preclinical studies suggested that there are correlations between resistant to therapies and TP53 alterations in mCRC [40][41][42] . Our results showed that liver ECs induced HER3-AKT activation and cell survival in all cell lines we used, which harbor either wild-type or mutant TP53.…”