Analysis of Molecular Pretreated Tumor Profiles as Predictive Biomarkers of Therapeutic Response and Survival Outcomes after Neoadjuvant Therapy for Rectal Cancer in Moroccan Population

Abstract

Pathologic features depending on tumor response to preoperative chemoradiotherapy are important to determine the outcomes in patients with rectal cancer. Evaluating the potential predictive roles of biomarker expression and their prognostic impact is a promising challenge. We reported here the immunohistochemical staining of a panel marker of mismatch repair protein (MMR), Ki67, HER-2, and p53. Additionally, identification of somatic mutations of KRAS, NRAS, and BRAF genes were performed by direct sequencing and pyrosequencing in pretreated biopsy tissues from 57 patients diagnosed for rectal cancer. Clinical features and pathological criteria for postneoadjuvant treatment surgical resection specimen’s data were collected. Immunohistochemical expression and mutational status were correlated with therapeutic response, overall survival, and disease progression. The mean age of patients was 56 years. Seven (12.3%) out of 57 patients had a complete therapeutic response. Our analysis showed that when using complete therapeutic response (Dworak 4) and incomplete therapeutic response (Dworak 3, 2, and 1) as grouping factor, high p53 expression at the pretreatment biopsy was significantly associated to an incomplete response (p=0.002). For 20 and 2 out of 57, KRAS and NRAS mutations were detected, respectively. The majority of these mutations affected codon 12. KRAS mutations detected at codon 146 (A146T, A146V) was associated with the appearance of recurrence and distant metastasis (p=0.019). A high expression of HER-2 corresponding to score 3+ was observed in 3 pretreatment biopsy specimens. This class was significantly associated with a short relapse-free survival (p=0.002). Furthermore, the high expression of Ki67 was moderately correlated with an older age (p=0.016, r=0.319). In addition, this shows that high p53 expression in the pretreatment biopsy was associated with an incomplete response in surgical resection specimens after neoadjuvant treatment, and a HER-2 score 3+ can be a predictive factor of distant metastasis and local recurrence. Larger, prospective, and more studies are needed.

Tissue-Based Markers as a Tool to Assess Response to Neoadjuvant Radiotherapy in Rectal Cancer—Systematic Review

“…Lopez et al found that, although 50% of the patients had mutations in TP53, no correlation between changes of p53 in cancer tissue and different responses to radiotherapy was found [ 74 ]. Another study on the Moroccan population found a high expression of p53 in tumor tissue in 93% (39) of patients with an incomplete response and in only 7% of complete responders, demonstrating that p53 may be of prognostic value in the therapeutic response of LARC [ 75 ]. Similarly, Hur et al found that 46.9% of patients with low-expressed p53 in their tumor tissue achieved pCR, whereas only 24.5% of patients with overexpressed p53 were able to achieve pCR [ 76 ].…”

Clinical significance of proliferation index and E-cadherin expression in colorectal adenocarcinoma

“…In this study, no significant association was found between Ki67/proIDX expression with gender, age of the subjects, localization of the tumor in the colon and with the histological grade of colorectal cancer. However, there is an observation in the literature about a significant correlation the high expression of Ki67 with an older age of patients [17].…”

Evaluating whether KRAS/BRAF mutation status, anaemia and obstruction are associated with recurrence and mortality in non‐metastatic colorectal cancer

“…El Otmani et al 6 found that in rectal cancer patients, KRAS mutations at codon 146 were associated with increased recurrence rates and distant metastases, but there was no significant association with overall survival. In this study, BRAF mutations were absent in pretreated tumour biopsies.…”