Reviews & Analysis

The recently updated breast cancer screening guidelines from the American Cancer Society are less aggressive than previous versions and clearer about overdiagnosis. However, a lack of attention was placed on the differences in effect estimates between trials at high and low risk of bias, and the authors failed to quantify the most serious harm.

Henderson and colleagues previously highlighted the need for more-rigorous standards of preclinical experimental design and reporting metrics. They now build on their earlier work with a meta-analysis of preclinical experiments that examined the efficacy of sunitinib. Their results demonstrate how suboptimal preclinical study designs can prompt unwarranted clinical expectations.

Surgeons should promote the best standard of surgical care through evidence-based results from prospective trials. European surgical investigators, in this issue of the journal, highlight the difficulties in patient accrual to surgical trials, patient and physician biases, and referral and quality assurance hurdles. We expand on these points and suggest some solutions.

The results of three recent studies demand that more attention be placed on defining the most-appropriate approach to population-based breast-cancer screening, in particular regarding the potential harms of increasing overdiagnosis. Two of these studies report that more-sensitive detection of breast neoplasms is possible by 3D tomography and by MRI, but the third paper raises the question of whether this increased sensitivity is desirable.

A study assessing the impact of the 21-gene recurrence score assay in routine clinical practice on the use of adjuvant chemotherapy in women with early stage ER-positive breast cancers showed that adjuvant chemotherapy use decreased in high-risk patients, but increased in low-risk patients. I discuss these results and highlight how this reflects more-selective administration of chemotherapy.

In the RADIANT study, no difference in disease-free survival was observed for patients with non-small-cell lung cancer (NSCLC) treated with erlotinib versus placebo in the adjuvant setting. Further biomarker studies are awaited to determine whether patients with NSCLC can benefit from adjuvant therapy with tyrosine kinase inhibitors.

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.

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.

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.

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.

Taxane-based regimens are among the preferred first-line chemotherapy options for metastatic breast cancer, with weekly paclitaxel considered equivalent to 3-weekly docetaxel. The CALGB 40502/NCCTG N063H (Alliance) trial has now compared bevacizumab plus weekly paclitaxel, nab-paclitaxel, or ixabepilone in this setting; ixabepilone was inferior and nab-paclitaxel was not superior, with a trend towards inferiority. Paclitaxel thus remains the standard-of-care taxane chemotherapy.

An analysis of reports from phase III trials (published between 2011 and 2013) investigating patients with solid tumours found widespread failings in both the conduct and reporting of subgroup analyses. Readers might well be misled by such analyses. Editors should, therefore, implement policies to reduce the risk of publishing misleading results.

Risk-reducing salpingo-oophorectomy (RRSO) is a standard intervention in BRCA1 or BRCA2 mutation carriers owing to its associated reduction in mortality related to ovarian and breast cancer. A study has now reported a beneficial impact of adjuvant RRSO in patients with BRCA1 mutations and breast cancer. However, various biases confound these results.

Pancreatic cancer remains a difficult-to-treat malignancy, yet nab-paclitaxel plus gemcitabine prolongs survival. Closer examination of the mechanism of action of nab-paclitaxel hints at a role for targeting KRAS. We discuss how nab-paclitaxel may be active in pancreatic cancer and how this informs the way forward to better treat patients with pancreatic cancer.

The efficacy of immunotherapy in metastatic melanoma is established, with anti-CTLA-4 and anti-PD-1 antibody-based therapies providing unexpectedly high responses and prolonged survival. The combination of nivolumab and ipilimumab is now poised to become the new standard of care, based on a 61% response rate in a recent randomized extended phase I/II trial, confirmed by phase III data presented at ASCO 2015.

The results of the ENESTg1 trial confirm the efficacy of imatinib, but not nilotinib, as a first-line treatment for gastrointestinal stromal tumours (GISTs) harbouring sensitizing mutations in KIT or PDGFRA. Nilotonib might prove to be beneficial in other subset of patients; however, there remains an urgent unmet need to address the GIST subtypes that are therapeutic orphans.