Molecular profile in Paraguayan colorectal cancer patients, towards to a precision medicine strategy

Somatic mutation analysis and evaluation of microsatellite instability (MSI) have become mandatory for selecting personalized therapy strategies for advanced colorectal cancer and are not available as routine methods in Paraguay. The aims of this study were to analyze the molecular profile as well as the microsatellite status in a series of advanced colorectal patients from two public hospitals from Paraguay, to introduce these methodologies in the routine practice to guide the therapeutic decisions.CONACYT – Consejo Nacional de Ciencia y TecnologíaPROCIENCI

The prognostic potential of CDX2 in colorectal cancer: Harmonizing biology and clinical practice

Adjuvant chemotherapy following surgical intervention remains the primary treatment option for patients with localized colorectal cancer (CRC). However, a significant proportion of patients will have an unfavorable outcome after current forms of chemotherapy. While reflecting the increasing complexity of CRC, the clinical application of molecular biomarkers provides information that can be utilized to guide therapeutic strategies. Among these, caudal-related homeobox transcription factor 2 (CDX2) emerges as a biomarker of both prognosis and relapse after therapy. CDX2 is a key transcription factor that controls intestinal fate. Although rarely mutated in CRC, loss of CDX2 expression has been reported mostly in right-sided, microsatellite-unstable tumors and is associated with aggressive carcinomas. The pathological assessment of CDX2 by immunohistochemistry can thus identify patients with high-risk CRC, but the evaluation of CDX2 expression remains challenging in a substantial proportion of patients. In this review, we discuss the roles of CDX2 in homeostasis and CRC and the alterations that lead to protein expression loss. Furthermore, we review the clinical significance of CDX2 assessment, with a particular focus on its current use as a biomarker for pathological evaluation and clinical decision-making. Finally, we attempt to clarify the molecular implications of CDX2 deficiency, ultimately providing insights for a more precise evaluation of CDX2 protein expression

Gastric metaplasia as a precursor of nonconventional dysplasia in inflammatory bowel disease

Gastric metaplasia in colonic mucosa with inflammatory bowel disease (IBD) develops as an adaptation mechanism. The association between gastric metaplasia and nonconventional and/or conventional dysplasia as precursors of colitis-associated colorectal cancer is unknown. To address this question, we retrospectively reviewed a series of 33 IBD colectomies to identify gastric metaplasia in 76 precursor lesions. We obtained 61 nonconventional and 15 conventional dysplasias. Among nonconventional dysplasia, 31 (50.8 %) were low-grade (LGD), 4 (6.5 %) were high-grade (HGD), 9 (14.8 %) had both LGD and HGD, and 17 (27.9 %) had no dysplasia (ND), while 14 (93 %) conventional dysplasias had LGD, and 1 (7 %) had LGD and HGD. Gastric metaplasia was assessed by concomitant immunoexpression of MUC5AC and loss of CDX2 staining. Expression of a p53-mut pattern was considered as a surrogate for gene mutation, and complete loss of MLH1 staining as presence of MLH1 hypermethylation. In nonconventional dysplasia, MUC5AC immunoexpression decreased as the degree of dysplasia increased, being 78 % in LGD and 39 % in HGD (p = 0.006). CDX2 was lost in epithelial glands with high expression of MUC5AC (p < 0.001). The p53-mut pattern was observed in 77 % HGD, 45 % LGD, and in 6 % with ND (p < 0.001). Neither nonconventional nor conventional dysplasia showed complete loss of MLH1 staining. Gastric metaplasia was also present in mucosa adjacent to nonconventional dysplasia with chronic changes or active inflammation. Our results show that gastric metaplasia appears in IBD-inflamed colon mucosa, it is the substrate of most nonconventional dysplasia and occurs prior to p53 alterations

Alterations in p53, Microsatellite Stability and Lack of MUC5AC Expression as Molecular Features of Colorectal Carcinoma Associated with Inflammatory Bowel Disease

Colitis-associated colorectal carcinoma (CAC) occurs in inflammatory bowel disease (IBD) because of the "chronic inflammation-dysplasia-cancer" carcinogenesis pathway characterized by p53 alterations in the early stages. Recently, gastric metaplasia (GM) has been described as the initial event of the serrated colorectal cancer (CRC) process, resulting from chronic stress on the colon mucosa. The aim of the study is to characterize CAC analyzing p53 alterations and microsatellite instability (MSI) to explore their relationship with GM using a series of CRC and the adjacent intestinal mucosa. Immunohistochemistry was performed to assess p53 alterations, MSI and MUC5AC expression as a surrogate for GM. The p53 mut-pattern was found in more than half of the CAC, most frequently stable (MSS) and MUC5AC negative. Only six tumors were unstable (MSI-H), being with p53 wt-pattern (p = 0.010) and MUC5AC positive (p = 0.005). MUC5AC staining was more frequently observed in intestinal mucosa, inflamed or with chronic changes, than in CAC, especially in those with p53 wt-pattern and MSS. Based on our results, we conclude that, as in the serrated pathway of CRC, in IBD GM occurs in inflamed mucosa, persists in those with chronic changes and disappears with the acquisition of p53 mutations

Targeted immunotherapy against distinct cancer-associated fibroblasts overcomes treatment resistance in refractory HER2+ breast tumors

About 50% of human epidermal growth factor receptor 2 (HER2)+ breast cancer patients do not benefit from HER2-targeted therapy and almost 20% of them relapse after treatment. Here, we conduct a detailed analysis of two independent cohorts of HER2+ breast cancer patients treated with trastuzumab to elucidate the mechanisms of resistance to anti-HER2 monoclonal antibodies. In addition, we develop a fully humanized immunocompetent model of HER2+ breast cancer recapitulating ex vivo the biological processes that associate with patients' response to treatment. Thanks to these two approaches, we uncover a population of TGF-beta-activated cancer-associated fibroblasts (CAF) specific from tumors resistant to therapy. The presence of this cellular subset related to previously described myofibroblastic (CAF-S1) and podoplanin+ CAF subtypes in breast cancer associates with low IL2 activity. Correspondingly, we find that stroma-targeted stimulation of IL2 pathway in unresponsive tumors restores trastuzumab anti-cancer efficiency. Overall, our study underscores the therapeutic potential of exploiting the tumor microenvironment to identify and overcome mechanisms of resistance to anti-cancer treatment

Molecular profiling of advanced solid tumours. The impact of experimental molecular-matched therapies on cancer patient outcomes in early-phase trials: the MAST study

Molecular-matched therapies have revolutionized cancer treatment. We evaluated the improvement in clinical outcomes of applying an in-house customized Next Generation Sequencing panel in a single institution