Reviews & Analysis

ROS1 fusions can be identified across a range of malignancies and confer a high level of sensitivity to ROS1 tyrosine kinase inhibitors. Herein, the authors discuss the non-malignant and malignant biology of ROS1, the diagnostic approaches to identifying ROS1 fusions and the current therapeutic concepts relating to ROS1 fusion-positive cancers, including the resistance mechanisms that have emerged with current ROS1 inhibitors.

The efficacy of chemotherapy in patients with cancer is now known to have an immunogenic component. Nonetheless, chemotherapy alone often fails to provide durable disease remission in most patients. The development of immune checkpoint inhibitors has created an opportunity to combine immunogenic chemotherapies with these agents in order to optimize patient outcomes. In this Review, the authors describe the mechanisms of synergy between chemotherapy and immune checkpoint inhibitors, summarize the available clinical data on these effects and highlight the most promising areas for future research.

Measuring the methylation status of cell-free DNA (cfDNA) in plasma holds great potential for the early, noninvasive detection of cancer. Two recent papers published in Nature Medicine showcase the successful application of cfDNA methylation-based cancer detection to two highly challenging scenarios.

TGFβ released by cancer cells and other cells in the tumour microenvironment enables cancer cell invasion and dissemination, stem cell properties and therapeutic resistance as well as generating an immunosuppressive environment. The authors of this Review introduce the mechanisms underlying TGFβ signalling in tumours and their microenvironment and discuss approaches to inhibit these signalling mechanisms, in particular in the context of cancer immunotherapy.

SABR-COMET was the first randomized controlled trial to demonstrate an overall survival benefit with the use of stereotactic ablative body radiotherapy (SABR) for the treatment of oligometastatic cancer. Considering the recently reported long-term follow-up data from SABR-COMET, we review the outcomes and limitations of this study in the context of other emerging information on therapy for oligometastatic disease.

Photodynamic and photothermal therapies hold promise in the local treatment of cancer although, arguably, their full potential has not yet been achieved. Herein, the authors review the current clinical progress of these phototherapies and discuss the bioengineering approaches that are being explored to overcome challenges and thereby improve such treatments.

Most systemic cancer therapies are administered at doses at or close to the maximum tolerated dose until disease progression. However, this approach usually leads to treatment resistance and fails to take into account several potentially relevant evolutionary principles. In this Review, the authors describe how existing approaches to cancer therapy might be optimized by incorporating an understanding of evolutionary dynamics into cancer therapy.

The availability and subsequent successes of immune-checkpoint inhibitors (ICIs) in patients with metastatic melanoma, and to a lesser extent in those with several other forms of cancer, have made long-term treatment-free remissions a realistic possibility for a subset of patients. In this Perspective, the authors describe available data on long-term remission from patients with melanoma and other solid tumours and provide early recommendations regarding the circumstances in which ICIs can be safely discontinued.

The analysis of ctDNA obtained from low-volume blood samples has the potential to transform the management of patients with colorectal cancer. Nevertheless, research priorities and minimum standards for sample collection and analysis in this area are currently missing. In this Position Paper, the NCI Colon and Rectal–Anal Task Forces provide a set of recommendations designed to address these challenges and accelerate the implementation of ctDNA in the management of patients with colorectal cancer.

Immune-checkpoint inhibition has transformed the treatment of patients with advanced-stage cancers. Nonetheless, the specific antigens targeted by T cells that are activated or reactivated by these agents remain largely unknown. In this Review, the authors describe the characterization and classification of tumour antigens including descriptions of the most appropriate detection methods, and discuss potential regulatory issues regarding the use of tumour antigen-based therapeutics.

Risk-adapted approaches to breast cancer prevention and screening could potentially be more effective than universal approaches, which have important limitations. In this Consensus Statement, representatives of the European Collaborative on Personalized Early Detection and Prevention of Breast Cancer (ENVISION) discuss the current state of breast cancer risk prediction, risk-stratified prevention and early detection strategies, and their implementation. They also present the ENVISION recommendations on priorities for future research in each of these areas with the aim of stimulating and guiding risk-adapted breast cancer prevention and screening programmes.

Cell-free DNA and proteins are secreted into the bloodstream by multiple types of cancer. In a recently published prospective study involving 10,006 women, such markers were used in a cancer screening approach that incorporated PET–CT as a confirmatory test. Herein, we discuss the implications of these results.

Therapies are being developed to treat cancers on the basis of specific molecular alterations and markers of immune phenotypes that transcend specific tumour histologies. The authors summarize the development and testing of approved histology-agnostic therapeutic agents, present data on other agents under development and discuss the challenges intrinsic to histology-agnostic drug development in oncology, including biological, regulatory, design and statistical considerations.

Signalling induced by extracellular adenosine (eADO) can suppress antitumour immunity through multiple mechanisms. Herein, the authors review the pathophysiological functions of eADO in cancer and the related prognostic implications. They discuss the associated opportunities for eADO pathway-targeted immunotherapy, highlighting potential limitations and the scope for combination and biomarker-based strategies. The data emerging from oncology clinical trials of the diverse range of therapies that have been developed to target the eADO signalling pathway are also described.

Therapies targeting MET-overexpressing cancers have limited efficacy. However, owing to advances in detection methods, therapies targeting MET-dependent tumours harbouring MET amplifications, activating mutations or fusions are emerging. In this review, the authors describe emerging data on this new class of targeted therapies.

Monitoring both cancer incidence and death rates is important for guiding health policy and the direction of future research. In this Perspective, the authors describe changes in cancer incidence and death rates in the USA, highlighting the effects of specific policies and research developments, and providing insight into unmet needs that should be addressed by future health policies.

Lung cancer screening is currently based only on low-dose CT scans; however, novel, more accessible methods that might improve uptake and adherence are eagerly awaited. New liquid biopsy approaches promise to revolutionize cancer screening. Herein, we discuss the opportunities and challenges associated with two such novel assays.

Mature results of the PROfound study demonstrate that the poly(ADP-ribose) polymerase (PARP) inhibitor olaparib prolongs progression-free survival compared with second-generation hormonal therapies in men with metastatic castration-resistant prostate cancer harbouring BRCA1, BRCA2 or ATM mutations. However, a closer look at the efficacy of olaparib on a gene-by-gene basis suggests that its activity is most pronounced in BRCA2-mutant prostate cancers and might not be equally active in all homologous recombination repair-deficient cancers.

Bacteria within tumours affect progression and response to therapy; in addition, bacterial DNA can be detected in cell-free plasma. Herein, we discuss evidence showing that intratumoural bacteria are characteristic for each tumour type, and that detection of cell-free bacterial DNA in blood could provide an accurate and non-invasive test for cancer diagnosis.

Important research efforts are being made to develop therapeutic strategies targeting the tumour microenvironment in pancreatic adenocarcinoma. The authors of this Review describe the apparent contradiction between preclinical studies and clinical outcomes observed to date, presenting more sophisticated strategies under active investigation.