File Name: tumor heterogeneity and personalized medicine .zip
Liver cancer is one from the most lethal cancers, ranking second only to lung cancer in terms of its global mortality 1. Although there are potentially curative surgical treatments available for those presenting with earlier stage disease 2 - 4 , recurrence is common post resection and liver transplantation is limited by organ availability. Furthermore, the majority of patients have intermediate or advanced stage disease at diagnosis 2 - 5. For these individuals, locoregional therapies are considered where liver function and performance status are good. For those who progress, or who have more advanced disease at presentation, sorafenib was accepted as the standard of care following landmark trials published in 6 and 7. While sorafenib treatment was associated with only a modest median survival benefit of 2. Unfortunately, despite major investment in phase II and phase III trials over the last decade, predominantly assessing therapies targeting kinases and angiogenic pathways sunitinib, brivanib, linifanib, everolimus and erlotinib , none has—as yet—shown any survival benefit.
Perioperative chemotherapy remains critical in improving long-term disease-free and overall survival outcomes among patients with locally advanced yet surgically resectable gastroesophageal adenocarcinoma GEA. Fluorouracil, leucovorin, oxaliplatin, and docetaxel FLOT is a recognized standard treatment from the phase 3 FLOT4 trial, 1 but toxic effects limit its application to select patients such that doublet chemotherapy with fluorouracil, leucovorin, and oxaliplatin FOLFOX is also recommended in national guidelines. Thus, the report by Catenacci et al 3 presents a unique first application of this combination among patients with GEA that can be surgically resected with curative intent. Building on their work in the metastatic setting, Catenacci et al 3 pursued an up-front dose reduction of irinotecan for patients with genotyping results associated with diminished activity of the UGT1A1 enzyme. Although the known polymorphism in exon 1 of the UGT1A1 gene, which is also associated with diminished enzyme activity, was included in their assay platform, it was not found in any patients enrolled in the trial. However, the pharmacogenomic dosing used in this study can still serve as a framework in Asian countries, where GEA has higher incidence and both TA promoter repeats and exon 1 coding polymorphisms encompass the differing UGT1A1 genotypes. Regarding their observed efficacy outcomes, Catenacci et al 3 used the feasible and clinically relevant coprimary end points of margin-negative resection rate and pathologic response grade PRG, also commonly referred to as tumor regression grade [TRG] to power their single-group statistical analysis of 36 evaluable patients.
Skip to search form Skip to main content You are currently offline. Some features of the site may not work correctly. DOI: In the past 10 years, the number of tools available to treat cancer has increased, as has our understanding of what makes some cancers tick. The standard old-time cancer treatments were largely predicated on attacking DNA, an approach fueled by the belief that tumor cells divide more rapidly than normal cells.
Tumor Heterogeneity and Personalized Medicine. Dan L. Longo, M.D.. In the past 10 years, the number of tools avail-. able to treat cancer has.
While the tailoring of treatment to patients dates back at least to the time of Hippocrates ,  the term has risen in usage in recent years given the growth of new diagnostic and informatics approaches that provide understanding of the molecular basis of disease, particularly genomics. This provides a clear evidence base on which to stratify group related patients. In personalised medicine, diagnostic testing is often employed for selecting appropriate and optimal therapies based on the context of a patient's genetic content or other molecular or cellular analysis.
Following the completion of the Human Genome Project in , research in oncology has progressively focused on the sequencing of cancer genomes, with the aim of better understanding the genetic basis of oncogenesis and identifying actionable alterations. NGS provided a significant step forward in Personalized Medicine PM by enabling the detection of somatic driver mutations, resistance mechanisms, quantification of mutational burden, germline mutations, which settled the foundation of a new approach in cancer care. In this chapter, we discuss the history, available techniques, and applications of NGS in oncology, with a particular referral to the PM approach and the emerging role of the research field of pharmacogenomics. Cancer is a genetic disease.
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