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

Panitumumab: the evidence of its therapeutic potential in metastatic colorectal cancer care

Colorectal cancer is the fourth most common malignant disease. Of newly diagnosed patients, 40% have metastatic disease at diagnosis, and approximately 25% of patients with localized disease at diagnosis will ultimately develop metastatic disease. The benefits of systemic chemotherapy in the treatment of metastatic colorectal cancer over best supportive care have been established. Panitumumab (ABX-EGF) is the first fully human monoclonal antibody developed for use in colorectal cancer that targets the extracellular domains of epidermal growth factor receptor

Epigenetic mechanisms underlying prostate cancer radioresistance

Radiotherapy (RT) is one of the mainstay treatments for prostate cancer (PCa), a highly prevalent neoplasm among males worldwide. About 30% of newly diagnosed PCa patients receive RT with a curative intent. However, biochemical relapse occurs in 20-40% of advanced PCa treated with RT either alone or in combination with adjuvant-hormonal therapy. Epigenetic alterations, frequently associated with molecular variations in PCa, contribute to the acquisition of a radioresistant phenotype. Increased DNA damage repair and cell cycle deregulation decreases radio-response in PCa patients. Moreover, the interplay between epigenome and cell growth pathways is extensively described in published literature. Importantly, as the clinical pattern of PCa ranges from an indolent tumor to an aggressive disease, discovering specific targetable epigenetic molecules able to overcome and predict PCa radioresistance is urgently needed. Currently, histone-deacetylase and DNA-methyltransferase inhibitors are the most studied classes of chromatin-modifying drugs (so-called 'epidrugs') within cancer radiosensitization context. Nonetheless, the lack of reliable validation trials is a foremost drawback. This review summarizes the major epigenetically induced changes in radioresistant-like PCa cells and describes recently reported targeted epigenetic therapies in pre-clinical and clinical settings

Cetuximab every 2 weeks versus standard weekly dosing administration schedule

Dosing schedule; Efficacy; PharmacokineticsPrograma de dosificació; Eficàcia; FarmacocinèticaPrograma de dosificación; Eficacia; FarmacocinéticaCetuximab every 2 weeks (Q2W) dosing schedule is approved by the US FDA and by the Japanese Pharmaceuticals and Medical Devices Agency in patients with metastatic colorectal cancer and squamous cell carcinoma of the head and neck. Phase II trials have found comparable efficacy and safety for the weekly (Q1W) and Q2W schedules, and real-world studies have shown noninferiority of the Q2W compared with the Q1W schedule. Several guidelines recommend cetuximab Q2W administration as an alternative to the Q1W dosing schedule. Cetuximab Q2W can be administered with a Q2W dose of chemotherapy, making it a more convenient option to the Q1W schedule, potentially resulting in reduced costs for administration, increased flexibility for clinical staff and improved patient adherence

The Potential Role of Pharmacogenomic and Genomic in the Adjuvant Treatment of Early Stage Non Small Cell Lung Cancer

Although notable progress has been made in the treatment of non-small-cell lung cancer (NSCLC) in recent years, this disease is still associated with a poor prognosis. Despite early-stage NSCLC is considered a potentially curable disease following complete resection, the majority of patients relapse and eventually die after surgery. Adjuvant chemotherapy prolongs survival, altough the absolute improvement in 5-year overall survival is only approximately 5%

Holistic Approach to Immune Checkpoint Inhibitor-Related Adverse Events

Immune checkpoint inhibitors (ICIs) block inhibitory molecules, such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed cell death protein 1 (PD-1), or its ligand, programmed cell death protein ligand 1 (PD-L1) and enhance antitumor T-cell activity. ICIs provide clinical benefits in a percentage of patients with advanced cancers, but they are usually associated with a remarkable spectrum of immune-related adverse events (irAEs) (e.g., rash, colitis, hepatitis, pneumonitis, endocrine, cardiac and musculoskeletal dysfunctions). Particularly patients on combination therapy (e.g., anti-CTLA-4 plus anti-PD-1/PD-L1) experience some form of irAEs. Different mechanisms have been postulated to explain these adverse events. Host factors such as genotype, gut microbiome and pre-existing autoimmune disorders may affect the risk of adverse events. Fatal ICI-related irAEs are due to myocarditis, colitis or pneumonitis. irAEs usually occur within the first months after ICI initiation but can develop as early as after the first dose to years after ICI initiation. Most irAEs resolve pharmacologically, but some appear to be persistent. Glucocorticoids represent the mainstay of management of irAEs, but other immunosuppressive drugs can be used to mitigate refractory irAEs. In the absence of specific trials, several guidelines, based on data from retrospective studies and expert consensus, have been published to guide the management of ICI-related irAEs

The role of EGFR inhibitors in nonsmall cell lung cancer

The epidermal growth factor receptor is a cell membrane receptor that plays a key role in cancer development and progression. Ligand-activated epidermal growth factor receptor-dependent signaling is involved in cell proliferation, apoptosis, angiogenesis, invasion, and metastasis. Targeting the epidermal growth factor receptor represents a promising molecular approach in cancer treatment. Several antiepidermal growth factor receptor agents are in clinical development. This review focuses on the available clinical data on epidermal growth factor receptor-targeting drugs in the treatment of nonsmall cell lung cancer