Review Articles in 2015

A meaningful revolution in managing malignant diseases has occurred since the advent of molecular targeted therapies; while some agents have resulted in a clinical benefit, these novel agents are also associated with undesired effects and assessing these risks in the correct context of potential clinical benefit is paramount. The authors overview of the development and toxicity profiles of kinase inhibitors and monoclonal antibodies, with an emphasis on their clinical management, including patient supportive care needs, and the impact of these treatments use on the health-care expenditures at the end of life.

The presence of tumour-infiltrating lymphocytes (TILs) in breast tumours is related to a better prognosis in patients with early stage breast cancer, but the immunobiology of breast cancer remains to be well-characterized. In this Review, the authors discuss how to measure TIL-related parameters in the clinic, as well as their value as a prognostic and predictive biomarker in breast cancer. The rationale for enhancing immunity in breast cancer is also examined.

Acute myeloid leukaemia (AML) is a heterogeneous disease that is typically associated with a very poor prognosis; however, cytogenetic and molecular abnormalities that characterize different forms of AML have been used to better prognosticate patients and inform treatment strategies, which might enable better outcomes to be achieved. Moreover, in the era of next-generation sequencing and molecularly targeted therapy, genetic profiling of patients with AML could open new avenues of treatment. Herein, the authors discuss the evidence-base for integrating mutational data into treatment decisions for patients with AML, and propose novel therapeutic algorithms aimed at improving outcomes of this dismal disease by promoting clinical research.

The practice of palliative care for patients with cancer is continually improving, and an increasing evidence base indicates that early integration of oncological and palliative care can result in wide-ranging benefits for the patients, their loved ones, clinicians, and health-care payers. Herein, David Hui and Eduardo Bruera discuss optimization of clinical infrastructures, processes, and education to support this strategy, and provide a conceptual model for the integration of supportive and/or palliative care with primary and oncological care. The authors emphasize the need for health-care systems and institutions to tailor integration based on their resources, size, and the level of primary palliative care available.

Use of radiotherapy or chemotherapy generally increases the survival of women with breast cancer; however, the use of radiotherapy, chemotherapy agents, such as the anthracycline doxorubicin, or anti-HER2 agents, such as trastuzumab, confer an increased risk of adverse cardiovascular events in these patients. In this Review, the authors describe the incidence and management of treatment-induced cardiac disease in women with breast cancer, and highlight strategies that might be used to minimize this risk.

Tumour cells can evade the immune response through different strategies, with the tumour microenvironment being a key determinant of which pathways become activated to restrain antitumour immunity. The authors of this Review describe the four major types of therapeutic interventions required in combinations to generate a strong antitumour response. Importantly, they also discuss which combination therapies might effectively engage immunity to suppress tumour progression in four different scenarios defined by the composition of the immune tumour microenvironment.

As the numbers of available anticancer drugs and thus possible drug combinations continues to grow, determining the optimal toxicity–efficacy balance of treatment regimens becomes increasingly complex, and the utility of standard empirical approaches to optimizing drug dosing and scheduling is becoming increasingly limited. Mathematical modelling can substantially advance the development of effective treatment regimens through improved rationalization of therapeutic strategies. In this Review, the authors highlight the achievements that have been made to date in computational modelling of drug regimens, as well as the limitations of this approach. They also discuss the potential future implementation of this strategy to achieve precision medicine in oncology.

Chromosome instability (CIN) is gaining increasing interest as a central process in cancer, and is indicated whenever tumour cells harbour an abnormal quantity of DNA, termed 'aneuploidy'. In this Review, the authors review the literature published since 2000 that support the hypothesis that aneuploidy is a predictor of a poor prognosis in patients with cancer, focusing on the evidence from studies of seven common epithelial cancer types that performed multivariate analyses. The implications of ploidy analysis with regard to our theoretical understanding of the role of CIN in carcinogenesis, as well as its prognostic use in the clinic, are discussed.

Haematopoetic stem-cell transplantation (HSCT), has been the standard-of-care for eligible patients with chronic myeloid leukaemia (CML) for several decades. The development of tyrosine kinase inhibitors (TKIs) 15 years ago revolutionized the treatment of CML. For some patients, however, allogeneic HSCT remains the best treatment option. The authors of this Review discuss the current status of HSCT as a therapeutic option for CML management.

Cachexia, a syndrome where metabolic demands cannot be met by energy intake, can substantially reduce the quality of life and increase mortality of patients with oesophageal cancer. In this Review, authors describe the causes, and effects of cachexia in these patients throughout the disease trajectory, and during the survivorship period; suggestions are made on how best to manage the effects of, and minimize the occurrence of this syndrome.

The improved understanding of the molecular mechanisms that drive tumorigenesis has led to the development of molecularly targeted agents (MTAs) that inhibit specific proteins or pathways. However, the rate of drug approvals remains disappointingly low in oncology. The authors of this Review discuss several aspects of phase I trials that are evolving in the MTA era in order to adapt to the changing nature of cancer therapies and to expedite their clinical translation.

Several novel strategies have harnessed the ability of T cells to target cancer cells. Each treatment approach is based on unique platforms that should encourage development of further therapeutic agents in the future. The authors describe the background and development of distinct immunotherapy platforms, summarize the scientific advances in understanding the mechanism of action of each therapy, and discuss future strategies to improve these immunotherapies through enhanced engineering, biomarker selection, and mechanism-based combination regimens.

Genetic testing for cancer susceptibility remains focused on specific individuals identified based on their personal and family history of the disease. Wider population-based screening has been applied to specific groups with a known high prevalence of high-risk mutations in cancer-related genes. This Review describes the studies that support the feasibility and cost-effectiveness of this approach, with particular regard to testing for founderBRCA1/2mutations in Ashkenazi Jewish populations. These studies, together with the falling costs and increasing availability of genetic assays, advances in preventive medicine, and growing demand from individuals for their genetic information, have broadened interest in genetic testing for cancer susceptibility in increasingly large demographic groups; thus, the opportunities and challenges of the different potential population-based approaches that are predicated on specific genes, gene panels, the entire exome, or the whole genome are also discussed herein.

The molecularly targeted therapy paradigm has led to improvements in the management of patients with cancer. Responses to targeted therapies are, however, mostly short-lived, owing to inherent or acquired resistance, which in most cases relates to the outgrowth of pre-existent rare subclones harbouring resistance mutations. Our current understanding of this concept is reviewed herein; how knowledge of pre-existing resistance mechanism obtained through the use of ultra-sensitive sensitive DNA-sequencing assays might be best exploited to improve personalized medicine is discussed.

The incidence of cancer in transplant recipients is indisputably higher than that of the age-matched general population, and the increased cancer development in transplant recipients who require immunosuppression to avoid graft rejection is well recognized. This Review discusses the advances with mTOR inhibitors that interfere with tumour development via immune and non-immune mechanisms, and the current and future perspectives on how best to normalize the unacceptably high rates of post-transplantation malignancies are highlighted.

Cardiotoxic effects of chemotherapy can occur in various different ways depending upon the type of chemotherapy used and various patient characteristics. In this Review, the authors describe the established cardiotoxic effects of anthracyclines and HER2 inhibitors, and describe a systems medicine approach that might enable the optimal management of acute and chronic cardiotoxcities in patients who are receiving, or have received, these therapies.

Currently, more than a third of all breast cancers are nonpalpable at diagnosis, and this proportion is expected to increase owing to the expansion of effective breast-screening programmes. Surgical excision combined with axillary staging is the standard of care for patients with nonpalpable breast cancers, and requires accurate localization of the primary tumour prior to resection. This Review provides an overview of the various techniques available for the localization and surgical management of nonpalpable breast cancer, their advantages and disadvantages, and future directions for the development of new technologies.

Neurotoxicity caused by treatment is widely recognized in patients with cancer. This Review addresses the main neurotoxicities of cancer treatment with a focus on the newer therapeutics. Recognition of these patterns of toxicity is important because drug discontinuation or dose adjustment might prevent further neurological injury. Familiarity with the neurological syndromes associated with cancer treatments enables clinicians to use the appropriate treatment for the underlying malignancy while minimizing the risk of neurological damage, which might preserve patient quality of life.

Mucinous colorectal cancer has, in the past, been associated with inferior responses to treatment, and worse patient outcomes compared with other colorectal cancer subtypes; although, this situation has improved in the past 10–15 years. In this Review, the authors describe the key developments that have enabled these improvements, in addition to the potential for further improvements in the care of patients with mucinous colorectal cancer.

In the past, only patients with fully HLA-matched donors were able to benefit from blood or bone-marrow transplantation (BMT) for a variety of haematological malignancies. Owing to the development of a variety of immunomodulatory strategies, patients with no HLA-matched donor, who can therefore receive an HLA-haploidentical BMT, can expect the same or similar outcomes as those receiving HLA-matched BMT. In this Review, the authors describe the new approaches to immunomodulation that have made HLA-haploidentical BMT a realistic therapeutic approach.