Reviews & Analysis

In two recent phase III trials, investigators evaluated the addition of docetaxel to androgen-deprivation therapy for non-castrate prostate cancer. On the basis of the CHAARTED-trial findings, we can firmly conclude that this combination can be used in the metastatic setting. The results of the GETUG 12 trial are less informative, although some benefit for patients with high-risk localized prostate cancer was demonstrated.

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.

Repurposing approved, non-anticancer drugs is an attractive strategy for patients with cancer. To date, successes in oncology drug repurposing have been limited, despite strong evidence supporting the use of many different drugs. A lack of financial incentives for drug developers and limited drug development experience within the non-profit sector are key reasons for this lack of success. The authors discuss these issues and offer solutions to seize this opportunity in the interest of patients and societies, globally.

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.

Conducting high-quality prospective clinical trials in surgical oncology remains a challenge. The authors of this Perspectives examine some of the failures in published surgical oncology trials and discuss why they failed, and provide a critical assessment of the established prospective trial methodology in oncological practice and how these methods might be used more effectively in future evaluation of cancer-surgery practice.

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.

A recent objective study has demonstrated that the use of adjuvant platinum-based intraperitoneal chemotherapy in patients with small-volume residual advanced-stage ovarian cancer remains limited, despite the publication of several phase III trials demonstrating superior overall survival associated with this approach. Several factors might explain this far less than satisfactory state of affairs.

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.

Dose-expansion cohorts (DECs) enable investigators to identify potentially effective drugs, for specific patient populations, in a single trial by assessing antitumour activity as early as possible. We discuss how the objectives, design and interpretation of DEC have evolved, and how DECs are changing the landscape of early drug development.

Treatment with pembrolizumab, an anti-PD-1 antibody, improved progression-free survival compared with investigator-choice chemotherapy in a phase II trial in patients with advanced-stage melanoma previously treated with ipilimumab. Two subsequent independent trials have confirmed that anti-PD-1 therapy is a better option than either chemotherapy or ipilimumab in the frontline setting.

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.

Dairy cattle meat and milk factors are proposed as risks for colon and breast cancers. Several novel small circular DNAs that are genetically active in human cells have been isolated from bovine sera and milk. Such agents have also been detected in two lesions of multiple sclerosis. A unifying concept is presented putatively explaining the risks for these diseases that are associated with these factors.

Results of the UK Age trial suggest a significant benefit of annual mammography initiated at 39–41 years of age in preventing breast-cancer deaths occurring before the age of 50 years; however, this approach had no effect on the risk of breast-cancer death occurring before the age of 60 years and leads to prolonged deteriorations in quality of life owing to overdiagnosis.

A recent study has demonstrated that serial profiling of resistance mutations in cell-free DNA (cfDNA) collected from the blood of patients with colorectal cancer can be used to track tumour evolution throughout the therapeutic course. This approach has the potential to inform personalized medicine by enabling dynamic adaptation of therapy.

On the basis of an Early Breast Cancer Trialists' Collaborative Group meta-analysis, it has been suggested that the controversy over post-mastectomy radiotherapy (PMRT) for women with 1–3 involved lymph nodes should end. However, the meta-analysis lacks appropriate sample size, stratification, and uses outdated systemic regimens. Thus, the debate should continue.

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.

Human papillomavirus (HPV)-screening technologies and HPV vaccination are revolutionizing the management of cancers related to this virus, in particular, cervical neoplasms. At present, however, the effectiveness of these modalities is not optimal, owing to the limited scope of HPV-vaccination and cervical screening programmes. In this Perspectives, an international panel of experts describes for the first time a new campaign, termed 'HPV-FASTER', which aims to broaden the use of HPV vaccination coupled with HPV testing to women aged up to 30 years, and in some settings up to 50 years, with the aim of accelerating the reduction in the incidence of HPV infections and cervical cancer. The authors describe the evidence supporting this approach and details on how it might be implemented, discuss the opportunities—particularly in low-resource settings—and challenges associated with the strategy, and highlight key research gaps that need to be addressed in future studies.