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Fenton et al. Cancer Drug Resist 2018;1:200-3 I                                                         Page 201

               Unsatisfactory outcomes of systemic anti-cancer therapies in advanced, metastatic disease have also fuelled
               calls for better strategies for early diagnosis that detect cancer when it is still at a localised, manageable
               stage. However, biomarkers for the timely detection of most cancer types are currently still lacking [11-14] .
               Even if reliable biomarkers become available, early recognition may not always improve treatment outcome.
               For example, a mass screening programme for the early detection of neuroblastoma in children using
               vanillylmandelic acid as a biomarker was performed in Japan from 1985 to 2003. However, the programme
               was stopped because it resulted in an increased incidence of neuroblastoma but not in reduced mortality,
               indicating over diagnosis of cases that did not require therapy [15,16] . The benefit of mammography-based
               screening programmes for breast cancer is also currently under dispute. Studies suggest that for every
               woman whose life is prolonged through breast cancer screening, ten women receive unnecessary treatment.
               Many women lose subjectively healthy lifetime, because treatment outcome is the same as if therapy had
               started upon the onset of symptoms. False positive results cause anxiety to affected women. Finally, over-
               detection, -diagnosis and -treatment of patients who would never have developed a clinically relevant
               disease is an issue [14,17-20] .

               Of course, we do not dispute the value of understanding metastasis formation, or, of early detection in
               cancer. We simply emphasise that for the foreseeable future, there will be patients who are diagnosed
               with advanced disease that requires systemic therapy. Hence, there is an ongoing need to develop better
               therapies for such patients. The main obstacle to this is resistance. Improved strategies are urgently
               required for those cancers that either fail to respond altogether to treatment (“intrinsic” or “upfront”
               resistance), or stop responding during treatment (“acquired” resistance).

               Resistance to anti-cancer therapies is largely a consequence of the small therapeutic window often
               demonstrated by these treatments. The aim of every cancer therapy is to kill all cancer cells or at least
               to permanently stop their proliferation. In contrast to therapies designed to fight single cell pathogens
               (bacteria, fungi, parasites) or viruses, cancer cells are derived from host cells and do not offer specific
               (“foreign”) targets in the same way. Instead they differ in the expression level of genes and the activation
               status of pathways that are also present in normal cells. Hence, therapeutic drug concentrations are
               commonly associated with adverse events. Cytotoxic anti-cancer therapies typically interfere with basic
               cellular processes by inducing DNA damage or targeting the process of cell division. They are generally
               applied at the “maximum tolerated dose”, which makes further dosage increase impossible. Hence, even
               the formation of low-level resistance results in therapy failure [21-28] .

               Some protein kinase inhibitors (e.g., first-generation epidermal growth factor receptor and BCR-ABL
               inhibitors) and antibodies interfere more specifically with cancer abnormalities and are characterised
               by better tolerability. However, resistance formation may be an even bigger issue as cures are rare and
               resistance formation often inevitable [26,27,29-35] . This may be because it is easier for cancer cells to bypass
               their more selective impact, analogous to the rapid development of resistance to highly specific antiviral
               therapies; a well-known and recognised phenomenon [36-39] .

               Immunotherapies, in particular immune checkpoint inhibitors including cytotoxic T lymphocyte associate
               protein-4, programmed cell death 1 (PD-1), and PD-ligand 1, inhibitors have shown great promise for
               subgroups of patients suffering from specific forms of cancer including melanoma, renal-cell carcinoma,
               non-small-cell lung cancer, and head and neck cancer. Although these therapies are transformative for
               some patients, many do not benefit and long-term responses only occur in a minority of patients. The
               mechanisms underlying these differences are poorly understood, and biomarkers that would predict
               therapy response are lacking. In addition, immune checkpoint inhibitor-based therapies are also associated
               with severe adverse events. Hence, toxicity and resistance are also important issues during the development
               and improvement of such therapies [40-42] .
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