Reviews & Analysis

Adjuvant ipilimumab is associated with an 11% improvement in 5-year overall survival in patients with high-risk melanoma, but at the cost of considerable toxicity, with half of patients discontinuing treatment owing to adverse events. An analysis of quality-of-life (QoL) outcomes, however, showed little impact of adverse effects of this treatment on QoL, which is puzzling.

Early diagnosis is a key component of melanoma prevention, but diagnostic accuracy varies considerably among clinicians managing patients with potentially suspicious skin lesions. Several tools have been developed to objectively enhance diagnostic assessment and accuracy. Herein, we discuss the potential diagnostic value and limitations of GoogleNet Inception, a new tool for image-based classification of skin lesions.

The Cancer Genome Atlas Research Network recently published the most comprehensive, multi-omic molecular characterization of cervical cancers performed to date. The data reveal novel disease subtypes, and provide new insights into the aetiology and pathogenesis of cervical cancer. Importantly, the information obtained has potentially major clinical implications.

Adoptive cellular therapy (ACT) is now considered a bona fide treatment modality within the evolving field of anticancer immunotherapy. Great advances have enabled the adoptive transfer of tumour-selective lymphocytes for the treatment of a variety of malignancies. Unfortunately, this selectivity has led to the emergence of antigen-loss variants. New strategies need to be employed to minimize the incidence of this phenomenon, enabling the full potential of ACT to be realized.

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.

Fraser and colleagues describe the whole-genome sequencing (WGS) profiles of over 200 localized intermediate-risk prostate cancers. WGS has been widely used in research but not, thus far, in clinical settings. Herein, we consider the possible use of WGS in the field of precision oncology.

Patients with c-MET-expressing colorectal or gastrointestinal cancers generally have worse outcomes than those of patients whose tumours have low levels of, or absent c-MET expression. However, c-MET targeted agents have, thus far, failed to show clinical efficacy. In this Review, the authors describe the opportunities and challenges created by the clinical implementation of c-MET targeted therapies.

In less than a decade, the treatment landscape of metastatic melanoma has changed dramatically. Novel targeted agents and immunotherapies are revolutionizing patient outcomes, but the range of available drugs complicates clinical decision-making. Herein, the authors chart the therapeutic advances and review the current evidence that can be used to guide therapeutic decisions for individual patients with metastatic melanoma, highlighting knowledge gaps.

The success of cancer therapies is hampered by a paucity of suitable drug targets and the rapid development of therapy resistance. The concept of synthetic lethality provides a potential solution to these constraints via the identification of novel therapeutic vulnerabilities, as exemplified in two recent studies.

The costs of both newly approved, and established anticancer drugs have risen dramatically in the past decade, to the point where the costs of such treatments are becoming unsustainable. In this perspective, the authors outline the extent of this problem, and how it is likely to continue, while also suggesting measures that could be taken in future to address these rising costs.

Conventional radiotherapy with X-rays is being replaced by radiotherapy with high-energy charged particles, an approach that better spares healthy tissue from radiation but is associated with higher costs. Evidence supporting the cost-effectiveness of either modality can only come from the results of randomized clinical trials. The authors of this Review discuss ongoing randomized trials of charged-particle therapies as well as aspects related to radiobiology, which need to be taken into account in order to fully exploit the therapeutic potential of charged particles.

Analysis of circulating tumour components using liquid biopsy approaches holds considerable promise to improve the detection and treatment of cancer. In this Review, Alberto Bardelli and colleagues outline how different forms of liquid biopsy, and particularly the assessment of circulating tumour DNA, can be exploited to guide patient care, and discuss the progress made to date in integrating such analyses into the clinic.

The expansion of research and development of anticancer drugs in China has resulted in considerable delays in the approval of both clinical trials of novel agents, and the marketing approval of these agents once tested. In this Perspective, the authors describe the measures taken by the Chinese FDA to address these challenges in a rapidly developing research environment.

Data from the recent Stop 2G-TKI study confirm that around 60% of patients with chronic myeloid leukaemia who discontinue second-generation BCR–ABL1 tyrosine-kinase inhibitor (TKI) therapy after a sustained deep molecular response remain in remission for longer than 1 year. Importantly, the interim findings suggest that prior response to first-line TKI treatment might predict relapse risk after treatment discontinuation.

Clinical trial design has dramatically evolved with the advent of precision medicine. As a result, expedited drug-approval decisions have been made on the basis of evidence obtained in uncontrolled clinical trials. Herein, Saad et al. discuss the need to conduct randomized controlled trials at all phases of drug development in oncology, and present strategies to facilitate a seamless transition between phases of drug and/or biomarker development.

Tumour-associated macrophages (TAMs) are key drivers of tumour-promoting inflammation and cancer progression, and are important determinants of responsiveness to a range of therapies. Herein, the authors summarize the roles of TAMs in cancer, and discuss the potential of TAM-targeted therapeutic strategies to complement and synergize with other anticancer treatments.

By preventing the accumulation of misfolded or damaged proteins, the ubiquitin-proteasome pathway has essential functions in cell homeostasis. Cancer cells produce proteins that promote cell survival and proliferation, and inhibit cell death, and thus, clinical trials have tested the therapeutic effect of proteasome inhibitors on patients with a variety of cancer types, mainly haematological malignancies. Herein, the authors discuss the advances and challenges derived from the introduction of proteasome inhibitors in the clinic, including therapeutic resistance.

The interaction between radiotherapy and the host immune system has uncovered new mechanisms that can be exploited to improve the efficacy of radiotherapy. In this article, the authors highlight data providing new explanations for the success or failure of radiotherapy, and postulate, using radiation-induced tumour equilibrium (RITE) as an example, how the combination of immune-modulation and radiation could tip the balance of the host immune response to promote cure.

Intraoperative fluorescence enables highly specific real-time detection of tumours at the time of surgery. In particular, near-infrared (NIR) fluorescence is a promising tool currently being tested in clinical settings. Zhang et al. discuss the latest developments in NIR fluorophores, cancer-targeting strategies, and detection instrumentation for intraoperative cancer detection, as well as the challenges associated with their effective application in clinical settings.

Data obtained in the past year underscored the benefit of a triplet regimen comprising bortezomib, lenalidomide, and dexamethasone for patients with newly-diagnosed multiple myeloma, and have provided high-level evidence supporting the safety of adding daratumumab to standard-of-care doublets for those with relapsed and/or refractory disease. As a result, achieving minimal residual disease-negativity at any stage of myeloma is now a realistic possibility.