Clinical management of metastatic colorectal cancer in the era of precision medicine

Immunotherapy; Metastatic colorectal cancer; Precision medicineInmunoterapia; Cáncer colorrectal metastásico; Medicina de precisiónImmunoteràpia; Càncer colorectal metastàtic; Medicina de precisióColorectal cancer (CRC) represents approximately 10% of all cancers and is the second most common cause of cancer deaths. Initial clinical presentation as metastatic CRC (mCRC) occurs in approximately 20% of patients. Moreover, up to 50% of patients with localized disease eventually develop metastases. Appropriate clinical management of these patients is still a challenging medical issue. Major efforts have been made to unveil the molecular landscape of mCRC. This has resulted in the identification of several druggable tumor molecular targets with the aim of developing personalized treatments for each patient. This review summarizes the improvements in the clinical management of patients with mCRC in the emerging era of precision medicine. In fact, molecular stratification, on which the current treatment algorithm for mCRC is based, although it does not completely represent the complexity of this disease, has been the first significant step toward clinically informative genetic profiling for implementing more effective therapeutic approaches. This has resulted in a clinically relevant increase in mCRC disease control and patient survival. The next steps in the clinical management of mCRC will be to integrate the comprehensive knowledge of tumor gene alterations, of tumor and microenvironment gene and protein expression profiling, of host immune competence as well as the application of the resulting dynamic changes to a precision medicine-based continuum of care for each patient. This approach could result in the identification of individual prognostic and predictive parameters, which could help the clinician in choosing the most appropriate therapeutic program(s) throughout the entire disease journey for each patient with mCRC.Fortunato Ciardiello was supported by a grant from Regione Campania (I-Cure Research Project Cup 21C17000030007). Andres Cervantes was supported by grants from the Instituto de Salud Carlos III (PI18/01909 and PI21/00689). Fortunato Ciardiello reports institutional research grants from Amgen, Merck KGaA, Merck Sharp & Dohme, Pfizer, Pierre Fabre, Roche, and Servier; and service on advisory boards for Bayer, Merck KGaA, Merck Sharp & Dohme, Pierre Fabre, Roche, and Servier outside the submitted work. Davide Ciardiello reports a travel grant from Sanofi outside the submitted work. Stefania Napolitano reports honoraria from Bristol Myers Squibb and Novartis outside the submitted work. Josep Tabernero reports advisory board or scientific consultancy fees from Array Biopharma, AstraZeneca, Avvinity, Bayer, Boehringer Ingelheim, Chugai, Daiichi-Sankyo, Roche, Genentech, HalioDX SAS, Hutchison MediPharma International, Ikena Oncology, Inspirna Inc, IQVIA, Lilly, Menarini, Merck KGaA, Merus, Merck Sharp & Dohme, Mirati, Neophore, Novartis, Ona Therapeutics, Orion Biotechnology, Peptomyc, Pfizer, Pierre Fabre, Samsung Bioepis, Sanofi, Seattle Genetics, Scandion Oncology, Servier, SotioBiotech, Taiho, Tessa Therapeutics, and TheraMyc outside the submitted work. Andres Cervantes reports institutional research grants from Genentech, Merck KGaA, Bristol Myers Squibb, Merck Sharp & Dohme, Roche, Beigene, Bayer, Servier, Lilly, Novartis, Takeda, Astellas, Takeda, and Fibrogen; and honoraria or speaker’s fees from Amgen, Merck KGaA, Roche, Bayer, Servier, and Pierre Fabre outside the submitted work. Giulia Martini reports no conflicts of interest

Receptor tyrosine kinase-dependent PI3K activation is an escape mechanism to vertical suppression of the EGFR/RAS/MAPK pathway in KRAS-mutated human colorectal cancer cell lines

Colorectal cancer; Epidermal growth factor receptor (EGFR); MAPK pathwayCàncer colorectal; Receptor epidèrmic de factor del creixement (EGFR); Via MAPKCáncer colorrectal; Receptor epidérmico de factor del crecimiento (EGFR); Vía MAPKBACKGROUND: Previous studies showed that the combination of an anti-Epidermal growth factor (EGFR) and a MEK-inhibitor is able to prevent the onset of resistance to anti-EGFR monoclonal antibodies in KRAS-wild type colorectal cancer (CRC), while the same combination reverts anti-EGFR primary resistance in KRAS mutated CRC cell lines. However, rapid onset of resistance is a limit to combination therapies in KRAS mutated CRC. METHODS: We generated four different KRAS mutated CRC cell lines resistant to a combination of cetuximab (an anti-EGFR antibody) and refametinib (a selective MEK-inhibitor) after continuous exposure to increasing concentration of the drugs. We characterized these resistant cell lines by evaluating the expression and activation status of a panel of receptor tyrosine kinases (RTKs) and intracellular transducers by immunoblot and qRT-PCR. Oncomine comprehensive assay and microarray analysis were carried out to investigate new acquired mutations or transcriptomic adaptation, respectively, in the resistant cell lines. Immunofluorescence assay was used to show the localization of RTKs in resistant and parental clones. RESULTS: We found that PI3K-AKT pathway activation acts as an escape mechanism in cell lines with acquired resistance to combined inhibition of EGFR and MEK. AKT pathway activation is coupled to the activation of multiple RTKs such as HER2, HER3 and IGF1R, though its pharmacological inhibition is not sufficient to revert the resistant phenotype. PI3K pathway activation is mediated by autocrine loops and by heterodimerization of multiple receptors. CONCLUSIONS: PI3K activation plays a central role in the acquired resistance to the combination of anti-EGFR and MEK-inhibitor in KRAS mutated colorectal cancer cell lines. PI3K activation is cooperatively achieved through the activation of multiple RTKs such as HER2, HER3 and IGF1R

Case report of unusual synchronous anal and rectal squamous cell carcinoma: clinical and therapeutic lesson

Synchronous tumors of the rectum and anus are sporadic. Most cases in the literature are rectal adenocarcinomas with concomitant anal squamous cell carcinoma. To date, only two cases of concomitant squamous cell carcinomas of the rectum and anus are reported, and both were treated with up-front surgery and received abdominoperineal resection with colostomy. Here, we report the first case in the literature of a patient with synchronous HPV-positive squamous cell carcinoma of the rectum and anus treated with definitive chemoradiotherapy with curative intent. The clinical-radiological evaluation demonstrated complete tumor regression. After 2 years of follow-up, no evidence of recurrence was observed

Retrospective Study of Regorafenib Versus TAS-102 Efficacy and Safety in Chemorefractory Metastatic Colorectal Cancer (mCRC) Patients: A Multi-institution Real Life Clinical Data

INTRODUCTION: There have been significant developments in colorectal cancer (CRC) research over the last few years, with the introduction of new agents that have been prolonged median overall survival of metastatic colorectal cancer (mCRC). These therapies have improved patient outcomes; however, despite significant progress in strategies for cancer treatment, their use is limited by development of resistant mechanism. Almost 30% of patients with refractory mCRC will remain good candidates for further treatment. Regorafenib and TAS-102 are novel antitumor agents for patients with refractory mCRC. However, it is unclear which patients may derive a survival benefit from these drugs in real-life clinical practice.; METHODS: We performed a retrospective analysis evaluating safety and efficacy of TAS-102 and regorafenib in a cohort of refractory mCRC patients, in 3 different centers between January 1 2018 and May 31 2020, with the aim of assessing the optimal sequence treatment for these 2 drugs.; RESULTS: One hundred and forty mCRC patients were included in the analysis. Of these patients, 64 received regorafenib and 76 received TAS-102 as first treatment. After progression, in the regorafenib 24 (37%) patients switched to secondary treatment with TAS-102, instead, in the TAS-102 group, among 76 patients, 29 (45%) patients switched to secondary treatment with regorafenib. Disease control was achieved in 8 (12.5%) of 64 patients in the regorafenib group and 17 (22.4%) of 76 patients in the TAS-102 group. In terms of efficacy, the PFS and OS were similar in both treatment groups for primary and secondary treatments. AEs reported in this analysis were mostly consistent with the known safety profiles of regorafenib and TAS-102 in previous clinical trials.; CONCLUSION: The present study is the first one to compare the activity of the two agents in a large cohort of chemo-refractory mCRC patients providing more details about the best sequence, to be incorporated in clinical practice. Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved

Treatment of Cutaneous Melanoma Harboring SMO p.Gln216Arg Mutation with Imiquimod: An Old Drug with New Results

: Melanoma is the most lethal form of skin cancer and its incidence is growing worldwide. In the last ten years, the therapeutic scenario of this disease has been revolutionized by the introduction of targeted therapies and immune-checkpoint inhibitors. However, in patients with many lesions and bulky tumors, in which surgery is no longer feasible, there is a need for new treatment options. Here we report, for the first time to our knowledge, a clinical case where a melanoma patient harboring the SMO p.Gln216Arg mutation has been treated with imiquimod, showing a complete and durable response. To better explain this outstanding response to the treatment, we transfected a melanoma cell line (MeWo) with the SMO p.Gln216Arg mutation in order to evaluate its role in response to the imiquimod treatment. Moreover, to better demonstrate that the antitumor activity of imiquimod was due to its role in suppressing the oncogenic SMO signaling pathway, independently of its immune modulating function, an in vivo experiment has been performed. This clinical case opens up a new scenario for the treatment of melanoma patients identifying a new potentially druggable target

Receptor tyrosine kinase-dependent PI3K activation is an escape mechanism to vertical suppression of the EGFR/RAS/MAPK pathway in KRAS-mutated human colorectal cancer cell lines

Abstract BACKGROUND: Previous studies showed that the combination of an anti-Epidermal growth factor (EGFR) and a MEK-inhibitor is able to prevent the onset of resistance to anti-EGFR monoclonal antibodies in KRAS-wild type colorectal cancer (CRC), while the same combination reverts anti-EGFR primary resistance in KRAS mutated CRC cell lines. However, rapid onset of resistance is a limit to combination therapies in KRAS mutated CRC. METHODS: We generated four different KRAS mutated CRC cell lines resistant to a combination of cetuximab (an anti-EGFR antibody) and refametinib (a selective MEK-inhibitor) after continuous exposure to increasing concentration of the drugs. We characterized these resistant cell lines by evaluating the expression and activation status of a panel of receptor tyrosine kinases (RTKs) and intracellular transducers by immunoblot and qRT-PCR. Oncomine comprehensive assay and microarray analysis were carried out to investigate new acquired mutations or transcriptomic adaptation, respectively, in the resistant cell lines. Immunofluorescence assay was used to show the localization of RTKs in resistant and parental clones. RESULTS: We found that PI3K-AKT pathway activation acts as an escape mechanism in cell lines with acquired resistance to combined inhibition of EGFR and MEK. AKT pathway activation is coupled to the activation of multiple RTKs such as HER2, HER3 and IGF1R, though its pharmacological inhibition is not sufficient to revert the resistant phenotype. PI3K pathway activation is mediated by autocrine loops and by heterodimerization of multiple receptors. CONCLUSIONS: PI3K activation plays a central role in the acquired resistance to the combination of anti-EGFR and MEK-inhibitor in KRAS mutated colorectal cancer cell lines. PI3K activation is cooperatively achieved through the activation of multiple RTKs such as HER2, HER3 and IGF1R

Biomarker-Guided Anti-Egfr Rechallenge Therapy in Metastatic Colorectal Cancer

Anticossos monoclonals anti-EGFR; Càncer colorectal metastàticAnticuerpos monoclonales anti-EGFR; Cáncer colorrectal metastásicoAnti-EGFR monoclonal antibodies; Metastatic colorectal cancerThe prognosis of patients with metastatic colorectal cancer (mCRC) who progressed to the first and the second lines of treatment is poor. Thus, new therapeutic strategies are needed. During the last years, emerging evidence suggests that retreatment with anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (MAbs) in the third line of mCRC patients, that have previously obtained clinical benefit by first-line therapy with anti-EGFR MAbs plus chemotherapy, could lead to prolonged survival. The rationale beyond this “rechallenge” strategy is that, after disease progression to first line EGFR-based therapy, a treatment break from anti-EGFR drugs results in RAS mutant cancer cell decay, restoring the sensitivity of cancer cells to cetuximab and panitumumab. In fact, rechallenge treatment with anti-EGFR drugs has shown promising clinical activity, particularly in patients with plasma RAS and BRAF wild type circulating tumor DNA, as defined by liquid biopsy analysis at baseline treatment. The aim of this review is to analyze the current knowledge on rechallenge and to investigate the role of novel biomarkers that can guide the appropriate selection of patients that could benefit from this therapeutic strategy. Finally, we discuss on-going trials and future perspectives.Regione Campania (I-Cure Research Project, Grant number: Cup 21C17000030007), Gruppo Oncologico dell’Italia Meridionale (GOIM)

AXL is an oncotarget in human colorectal cancer

AXL is a tyrosine kinase receptor activated by GAS6 and regulates cancer cell proliferation migration and angiogenesis. We studied AXL as new therapeutic target in colorectal cancer (CRC). Expression and activation of AXL and GAS6 were evaluated in a panel of human CRC cell lines. AXL gene silencing or pharmacologic inhibition with foretinib suppressed proliferation, migration and survival in CRC cells. In an orthotopic colon model of human HCT116 CRC cells overexpressing AXL, foretinib treatment caused significant inhibition of tumour growth and peritoneal metastatic spreading. AXL and GAS6 overexpression by immunohistochemistry (IHC) were found in 76,7% and 73.5%, respectively, of 223 human CRC specimens, correlating with less differentiated histological grading. GAS6 overexpression was associated with nodes involvement and tumour stage. AXL gene was found amplified by Fluorescence in situ hybridization (FISH) in 8/146 cases (5,4%) of CRC samples. Taken together, AXL inhibition could represent a novel therapeutic approach in CRC

BRAF, MEK and EGFR inhibition as treatment strategies in BRAF V600E metastatic colorectal cancer

Inhibidor de BRAF; Binimetinib; Cáncer de colonBRAF inhibitor; Binimetinib; Colon cancerInhibidor de BRAF; Binimetinib; Càncer de còlonIntroduction: BRAF driver mutations are found in up to 15% of patients with colorectal cancer (CRC) and lead to constitutive activation of BRAF kinase and sustained RAS/RAF/MEK/ERK pathway signaling. BRAF mutations define a sub-population characterized by a poor prognosis and dismal median survival. Following successful outcomes with BRAF inhibition in BRAF mutant metastatic melanoma, this approach was evaluated in metastatic colorectal cancer (mCRC). The development and combination of targeted therapies against multiple signaling pathways has proved particularly successful, with improved survival and response rates. Areas covered: This review addresses the development of therapeutic strategies with inhibitors targeting MAPK/ERK and EGFR signaling in BRAF V600E mutated mCRC, focusing on encorafenib, binimetinib and cetuximab. A pharmacological and clinical review of these drugs and the therapeutic approaches behind their optimization are presented. Expert opinion: Exploiting knowledge of the mechanisms of resistance to BRAF inhibitors has been crucial to developing effective therapeutic strategies in BRAF-V600E mutant mCRC. The BEACON trial is a successful example of this approach, using encorafenib and cetuximab with or without binimetinib in patients with previously treated BRAF V600E mutant mCRC, showing an impressive improvement in clinical outcomes and tolerable toxicity compared with chemotherapy, establishing a new standard of care in this setting.The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by grants from Instituto de Salud Carlos III (ISCIII) FIS/FEDER (PI17/00947, PI20/00968) and from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 635342