Review Articles in 2018

Women with early-stage oestrogen receptor (ER)-positive (ER⁺) breast cancer remain at risk of distant recurrence for at least 15 years after discontinuation of 5 years of standard endocrine therapy. The authors of this Review discuss the epidemiology and mechanisms underlying late recurrence and examine several models used for risk prognostication and for estimating the presence of minimal residual disease.

Herein, advances in our understanding of the genomic landscape of childhood acute lymphoblastic leukaemia (ALL), encompassing both somatic and germline alterations, are reviewed. The clinical implications of these alterations, particularly those in the germ line, are discussed with regard to susceptibility to ALL, treatment responses and therapy-related toxicities.

The mechanisms of resistance to immunotherapy seem to broadly overlap with the immunoediting process whereby cancers evade detection by the immune system. The authors of this Review discuss these interactions as well as the strategies that can be used to overcome therapeutic resistance

Patients with cancer might be at a higher risk of nonmedical opioid use than was previously thought; however, opioid analgesics remain the gold standard to treat cancer-related pain. The authors of this Review examine the role of opioids in cancer-related pain, the risk of substance use disorder and methods to achieve the right balance between both to ensure safe opioid use.

Broad population screening of asymptomatic individuals for cancers of the prostate or thyroid has resulted in overdiagnosis and overtreatment. Herein, the authors describe the epidemiology, pathology, and screening guidelines for the management of patients with those cancers, and discuss existing international active surveillance protocols.

FGFR alterations can be detected in a small subset of many different cancer types. Inspired by the successes with other targeted therapies, preliminary attempts to target FGFR-altered cancers have been hampered by low response rates and acquired resistance. In this Review, the author describes the development of FGFR inhibitors thus far, and provides guidance on future research priorities.

A deterioration of disease can occur upon treatment with anti-PD-1/PD-L1 monoclonal antibodies; this paradoxical phenomenon is defined as hyperprogression. The authors discuss the pathophysiological hypotheses that might explain hyperprogressive disease and the resulting challenges for patient management, with a focus in clinical decisions involving immune-checkpoint inhibitors.

Inhibition of poly(ADP-ribose) polymerase (PARP) is the paradigmatic example of synthetic lethal therapy and is predicated on exploiting DNA repair deficiencies that are a hallmark of cancer. In this Review, the authors review the progress made to date with PARP inhibitors and describe the expanding landscape of novel anticancer therapies targeting the DNA damage response. Potential predictive biomarkers, mechanisms of resistance and combinatorial strategies are discussed.

Successful surgical resection offers patients with pancreatic cancer the best chance of survival. However, many patients do not have surgically resectable disease. In this Review, the authors describe recent improvements in pancreatic cancer surgery, which have increased survival and also enabled more patients to undergo surgery.

TRK fusion proteins are pathognomonic in certain rare tumour types and present in a small subset of diverse cancer types, including some common cancers; TRK inhibitors have promising efficacy in the treatment of these cancers, in a histology-agnostic manner. In this Review, the biology of TRK signalling and TRK fusions, strategies to target these drivers, the unique safety profile of TRK inhibitors and mechanisms of and strategies to overcome acquired resistance to these agents are discussed.

Effective therapeutic strategies to target RAS-mutant cancers have proved elusive, but in the past few years, several promising strategies have been tested in clinical trials. The authors describe historical and ongoing therapeutic approaches based on the direct or indirect targeting of RAS.

Intriguing evidence suggests that expression of RANK or RANKL by various cells of the tumour microenvironment modulates the anticancer immune response. Herein, the authors review this evidence, discuss the current preclinical and clinical data supporting a potential of RANKL inhibition to improve anticancer immunotherapy and describe hypothetical immune-related mechanisms of action.

Improvements in the management of patients with early stage breast cancer have been achieved through intense therapeutic escalation but also with de-escalation of systemic therapies. The authors of this Review summarize key trials using both approaches and highlight the need to use therapeutic escalation for patients who would benefit from that approach and de-escalation for patients with a favourable prognosis.

Androgen receptor (AR) splice variants (AR-Vs) are truncated isoforms of the AR, of which a subset remain constitutively active in the absence of circulating androgens. AR-Vs have been proposed to contribute to therapeutic resistance. The authors of this Review outline the current understanding of the role of the spliceosome in prostate cancer progression and explore the therapeutic utility of manipulating alternative splicing.

The clinical management of patients with non-small-cell lung carcinoma has greatly evolved owing to the development of tyrosine-kinase inhibitors (TKIs) targeted against the driver mutations of this disease. The authors of this Review describe the existing evidence on the sequential administration of TKIs and the use of next-generation TKIs upfront.

Molecular profiling studies are providing novel insights into the biology of hepatocellular carcinoma, although these remain to be translated into novel effective therapies. Nevertheless, therapeutic advances have been made in the past few years, and further advancements are expected in the near future, including biomarker-driven treatments and immunotherapies, as discussed in this Review.

The majority of patients receiving immunotherapy do not respond to treatment but might still have adverse events. Furthermore, some patients with an initial response will develop acquired resistance to treatment. In this Review, the authors describe the role of circulating tumour DNA in the management of patients receiving immunotherapy.

Following the success of poly(ADP-ribose) PARP inhibitors in patients with BRCA1/2 mutations, considerable research interest has emerged in the discovery of alternative forms of synthetic lethality. In this Review, the authors summarize the potential of various novel forms of synthetic lethality to further improve the treatment of patients with cancer.

The combination of radiotherapy and immune-checkpoint inhibition (ICI) has generated considerable excitement among oncologists, and numerous clinical trials are currently exploring the efficacy of this approach; however, the safety and tolerability of this combination remains incompletely understood. In this Review, the authors describe the available data on safety considerations in patients receiving radiotherapy in combination with ICI.

Emerging evidence indicates that tumour-derived extracellular vesicles (EVs), notably exosomes, mediate intercellular communication to promote cancer development and progression. Herein, the authors discuss EV properties and physiological functions, particularly their pro-metastatic effects, and highlight the diagnostic and therapeutic potential of EVs in cancer.