Reviews & Analysis

In the past, only patients with fully HLA-matched donors were able to benefit from blood or bone-marrow transplantation (BMT) for a variety of haematological malignancies. Owing to the development of a variety of immunomodulatory strategies, patients with no HLA-matched donor, who can therefore receive an HLA-haploidentical BMT, can expect the same or similar outcomes as those receiving HLA-matched BMT. In this Review, the authors describe the new approaches to immunomodulation that have made HLA-haploidentical BMT a realistic therapeutic approach.

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.

Stage IV gastric cancer is incurable and has a very poor prognosis. Although palliative chemotherapy remains the standard of care, increasing evidence indicates that palliative surgery can provide a prognostic and symptomatic benefit. This Perspectives summarizes the recent evidence underpinning the medical and surgical management of incurable gastric cancer, and provides evidence-based recommendations on treatment strategies and avenues for future research.

Metronomic chemotherapy has shown promising efficacy and minimal toxicity in patients with advanced-stage breast cancer. Moreover, the low cost of this regimen represents an opportunity for its expanded utilization, especially in developing countries. In this Review, the authors discuss the key clinical advances, including new trial design, appropriate patient and end point selection, and the evolving rationale for metronomic chemotherapy combinations.

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.

Response to first-line therapy is a primary determinant of outcome in patients with metastatic colorectal cancer (mCRC). In the past decade, the development of antiangiogenic and anti-EGFR biologic agents, doublet and triplet chemotherapy regimens, and combinations of these treatment modalities has created not only new first-line treatment options, but also new challenges for the management of this disease. In this Perspectives, these advances and the confusion surrounding their implications are discussed. The authors attempt to address some of the challenges in clinical decision-making and propose an algorithm for personalized allocation of first-line treatments in patients with mCRC.

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.

Many breast cancer survivors experience long-term adverse effects of adjuvant systemic therapy, including cognitive decline. The decline of cognitive functions can have a detrimental impact on quality of life and might interfere with independent living. This Review discusses the tissue-selective side effects of endocrine therapies and specifically their impact on cognitive function. The critical issues that need to be addressed to best assess the cognitive effects of endocrine treatment in patients with breast cancer are highlighted.

The development of precision medicine for the management of metastatic breast cancer is an appealing concept; however, major scientific and logistical challenges hinder its implementation in the clinic. The authors discuss the limitations, including the identification of driver events, and the possible solutions to the application of precision medicine in the management of patients with metastatic disease, which include scaling-up the number of patients screened for identifying a genomic alteration, the clustering of genomic alterations into pathways, and the development of personalized medicine trials.

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 use of traditional Euclidean geometry can present challenges for analysis of image characteristics, particular those of extremely complex biological structures, obtained by medical and scientific imaging modalities. Fractal geometry is a potentially complementary mathematical approach that enables efficient estimation of geometrical complexity, and the irregularity of shapes and patterns. This Review introduces the concept of fractals and fractal geometry, and describes how analysis of fractal (non-integer) dimension and associated measurements, such as lacunarity (texture), can be performed and applied to the analysis of cancer. The authors discuss how fractal analysis might provide information on many diverse biological structures relevant to the natural history of lung cancer, which might prove useful for the diagnosis and management of this disease.

Tumour-promoting inflammation is an enabling characteristic of many cancers. Conversely, many cancers can cause inflammation. Inflammation in the tumour microenvironment arises from the interplay of many different inflammatory cells and mediators, many of which are potential treatment targets. Herein, the authors review our current knowledge of the interplay between inflammation and tumorigenesis and discuss the potential of treatments that target cancer-related inflammation.

Endocrine resistance will eventually develop in patients with ER-positive breast cancer receiving endocrine therapy. Several studies unveiled gain-of-function mutations in theESR1 gene in approximately 20% of patients with metastatic ER-positive disease who received endocrine therapies. These mutations lead to ligand-independent ER activity that promotes tumour growth, partial resistance to endocrine therapy, and potentially enhanced metastatic capacity. We discuss the contribution of ESR1mutations to the development of acquired endocrine resistance, and evaluate how mutated ER can be detected and targeted to overcome resistance and improve patient outcomes.

Although dramatic changes in the delivery of radiation therapy have occurred, the impact of radiobiology on the clinic has been far less substantial. New advances are uncovering some of the mechanistic processes that underlie the differences between the tumour and host tissue characteristics. The authors of this Review focus on how these processes might be targeted to improve the outcome of radiotherapy for patients.

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.

Liver cancer mortality has increased in the past 20 years, and estimates indicate that the global health burden of this disease will continue to grow. Advances in our knowledge of the human genome have provided a comprehensive picture of commonly mutated genes in patients with hepatocellular carcinoma (HCC). In this Review, the authors summarize the molecular concepts of progression of HCC, discuss the potential reasons for clinical trial failure, and propose new concepts of drug development.

Despite the commercialization of HPV vaccines, cervical cancer remains a major cause of death, especially in developing countries. Recent data implicate a discrete population of cells within the cervical squamocolumnar junction in the pathogenesis of cervical precancerous lesions, indicating that ablation of these cells might reduce the rate of cervical cancer in high-risk populations.

In a recent international phase III trial, addition of bortezomib to a R-CHOP-like immunochemotherapy regimen for the first-line treatment of mantle-cell lymphoma resulted in a clinically meaningful extension of median progression-free survival. This finding emphasizes the role of targeted therapies in a relatively chemotherapy-refractory disease; however, therapeutic recommendations have to consider the observed haematotoxicity of this combination.

Randomized trial data support the use of laparoscopic surgery for colon cancer; however, such evidence was lacking for rectal cancer. Now, the COLOR II randomized trial gives minimally invasive resection of rectal cancer the 'green light', answering the question 'should laparoscopic surgery be used?' The new key question is 'who should be performing laparoscopic surgery for rectal cancer?'