Review Articles in 2017

Despite the achievement of locoregional control, a third of patients undergoing surgery for cancer will have disease recurrence. In this Review, the authors describe the potential to optimize the outcomes of patients with cancer by minimizing inflammation and activation of the sympathetic nervous system in the perioperative period, which is often achievable with simple and cost-effective changes in patient-management strategies.

Surgery remains the mainstay of treatment for patients with gliomas, independent of tumour grade, and maximal resection of the tumour is essential for long-term disease control. Herein, the authors discuss the current evidence on associations between the extent of glioma resection and clinical outcomes. They also describe the state-of-the-art surgical oncology approaches aimed at maximizing the extent of tumour resection while minimizing patient morbidity.

The receptor-tyrosine kinase RET has been identified as a potentially actionable driver of oncogenesis. Several multikinase inhibitors with activity against RET have been explored in the clinic, but have only modest efficacy in patients with thyroid cancers, mostly in those withRET mutations, or RET-rearranged lung cancers. Herein, the authors outline the aberrations in RET that contribute to tumorigenesis, review the current clinical data for inhibitors of this kinase, and discuss whether the limited clinical success achieved with these agents to date is attributable to the intractability of RET as a drug target or the lack of highly specific RET inhibitors.

The onset of acquired resistance to treatment is virtually inevitable in patients with solid tumours. In this Review, the authors describe the role of tumour heterogeneity in the development of acquired resistance, potential treatment strategies that take into account the heterogeneity of patient's tumours, and how a better understanding of tumour heterogeneity might improve the outcomes of patients.

Clinical trials are an essential aspect of drug development; however, in patients with non-castrate prostate cancer, the long natural history of the disease provides a major barrier to the introduction of new therapies. In this Review, the authors describe the potential of a novel, multi-arm, multistage, clinical trial project, with surrogate end points designed to fully reflect the effects of treatments, in transforming the treatment of patients with early stage prostate cancer, before the development of castration-resistant disease.

Cholangiocarcinoma, the second most common form of liver cancer after hepatocellular carcinoma, is a heterogeneous disease entity with a near-universal poor prognosis. Our understanding of the epidemiology and biology of cholangiocarcinoma is increasing, and importantly, potentially actionable molecular and immunological targets for novel therapies are increasingly being identified. Herein, the evolving developments in the epidemiology, pathogenesis, and management of cholangiocarcinoma are reviewed.

Radiomics is the high-throughput mining of quantitative image features from standard-of-care medical imaging to enable data to be extracted and applied within clinical-decision support systems. The process of radiomics is described and its pitfalls, challenges, opportunities, and capacity to improve clinical decision making. The radiomics field requires standardized evaluation of scientific findings and their clinical relevance. This review provides guidance for investigations to meet this urgent need in the field of radiomics.

In the past decade, the importance of patient-reported outcomes (PROs) as a key measure of the quality of care delivered to patients with cancer has been acknowledged. PROs were used in the context of research studies, but growing evidence indicates that the incorporation of electronic PRO (ePRO) assessments into standard health-care settings can improve the quality of care delivered to patients with cancer. The authors of this Review discuss aspects related to PROs such as measurements, implementation challenges, and outcome improvements associated with their use.

TP53, encoding the tumour-suppressor p53, is the most frequently mutated gene across all human cancers. Similar to other transcription factors, p53 has proved notoriously difficult to target therapeutically; to date, no p53-targeted therapies have entered the clinic. The diversity ofTP53 mutations, which can be categorized across a spectrum of different functional classes, is increasingly recognized as an additional challenge to developing p53-directed treatments. Herein, Kanaga Sabapathy and David Lane review this 'rainbow of p53 mutants', and discuss the implications for anticancer therapies targeting p53 or directed by TP53status.

Chimeric antigen receptor (CAR)-T-cell therapies are showing great promise in the treatment of cancer, particularly B-cell malignancies, but are associated with characteristic, potentially fatal toxicities, principally cytokine-release syndrome, CAR-T-cell-related encephalopathy syndrome, and haemophagocytic lymphohistiocytosis/macrophage-activation syndrome. Herein, the CAR-T-cell-therapy-associated TOXicity (CARTOX) Working Group, comprising multidisciplinary investigators from various institutions with clinical experience in the use of a range of CAR-T-cell platforms, review these acute toxicities and provide monitoring, grading, and management recommendations.

Cell-based immunotherapies are showing great promise in the treatment of even the most treatment-refractory of haematological malignancies. Herein, Jennifer Brudno and James Kochenderfer review the results obtained to date with CAR-T-cell therapies for lymphoma. They also discuss what has been learned regarding the limitations of CAR-T-cell therapies and areas for improvement relating to toxicity management, the design of CAR-T-cell products, conditioning regimens, and combination therapies.

A wide range of gene fusions have been detected in solid tumours, and the products of these fusions, some of which result in constitutive activation of kinase signalling, can be targeted using tyrosine-kinase inhibitors. However, the development of acquired resistance is almost inevitable. In this Review, the authors describe strategies used to diagnose and treat patients with fusion-positive cancers.

The development of predictive biomarkers is complex and the non-systematic approach to biomarker development in HER2-positive breast cancer challenges the way translational research is performed. Women with very favourable prognostic features will likely prefer shorter courses of treatment and might enquire about the possibility to forego aggressive chemotherapy. Considering these legitimate needs, Gingras et al. review the results of more than a decade of translational research efforts in this disease.

Virtually all successful treatments of cancer either create, restore or enhance the antitumour immune response. Therefore, the specific features of the immune microenvironment, both before and after treatment, are important determinants of patients' outcomes. In this Review, the authors describe the influence of the immunological characteristics of the tumour microenvironment on responses to treatment in patients with a variety of cancers.

Few therapeutic options are currently available for patients with glioblastoma, which are associated with a poor prognosis. Therapies with monoclonal antibodies, alone or linked to cytotoxic payloads, are currently being explored in these patients. Herein, the authors summarize therapeutic strategies based on antibody–drug conjugates (ADCs), targeted against EGFR, and discuss key aspects such as the blood–brain barrier, resistance mechanisms, and the development of specific biomarkers.

The identification of the tissue of origin in patients with cancer of unknown primary (CUP) is an example of how epigenomics can be incorporated in clinical settings. Epigenetic and other molecularly-based diagnostic strategies have emerged to complement traditional diagnostic procedures, thereby improving the clinical management of patients with CUP. Herein, the authors present the latest data on strategies using epigenetics and other molecular biomarkers to guide therapeutic decisions involving patients with CUP, addressing a previously unmet need.

Patients receiving anticancer therapies based on immune-checkpoint blockade (ICB) often experience clinical benefits from such treatments, but unconventional patterns of response can be observed, emphasizing the importance of using a specific approach to evaluating responses to immunotherapy. Herein, the authors review the biological mechanisms underlying the response patterns associated with ICB, describe strategies for the assessments of such responses, and highlight the ongoing efforts to identify biomarkers to guide treatment with ICB.

Patients with early stage breast cancer have traditionally been assigned adjuvant systemic therapies on the basis of the clinical and histological characteristics of their disease. However, this approach often leads to overtreatment. In this Review, the authors describe the use of gene-expression signatures, some of which are already in clinical use, for determining the risks of recurrence and progression, and the most appropriate form of adjuvant therapy.

For three decades, the treatment of small-cell lung cancer (SCLC) has remained essentially unchanged, and patient outcomes remain dismal. In the past 5 years, however, advances in our understanding of the disease, at the molecular level, have resulted in the development of new therapeutic strategies, encompassing immunotherapies and novel molecularly targeted agents. Herein, authors review the breakthroughs that hold the promise to improve SCLC outcomes.

According to the cancer stem cell (CSC) paradigm, a minor subpopulation of cancer cells with stem-cell properties predominantly underlies tumour progression, therapy resistance, and disease recurrence. Notably, epithelial-to-mesenchymal transition (EMT) is implicated in these processes, and CSCs typically show markers of EMT-programme activation. Herein, the authors outline our current understanding of the links between the EMT programme, the CSC phenotype, metastasis, and drug resistance, and discuss the potential for therapeutic targeting of these facets of tumour biology.