The genomes of cancers deficient in mismatch repair contain exceptionally high numbers of somatic mutations. In a proof-of-concept study, we previously showed that colorectal cancers with mismatch repair deficiency were sensitive to immune checkpoint blockade with antibodies to programmed death receptor–1 (PD-1). We have now expanded this study to evaluate the efficacy of PD-1 blockade in patients with advanced mismatch repair–deficient cancers across 12 different tumor types. Objective radiographic responses were observed in 53% of patients, and complete responses were achieved in 21% of patients. Responses were durable, with median progression-free survival and overall survival still not reached. Functional analysis in a responding patient demonstrated rapid in vivo expansion of neoantigen-specific T cell clones that were reactive to mutant neopeptides found in the tumor. These data support the hypothesis that the large proportion of mutant neoantigens in mismatch repair–deficient cancers make them sensitive to immune checkpoint blockade, regardless of the cancers’ tissue of origin.

/pdf/mismatch-repair-deficiency-predicts-response-of-solid-tumors-2mgnsq9rdf.pdf

Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade

Glioblastoma is the most common primary malignant brain tumor in adults and is associated with poor survival. The Ivy Foundation Early Phase Clinical Trials Consortium conducted a randomized, multi-institution clinical trial to evaluate immune responses and survival following neoadjuvant and/or adjuvant therapy with pembrolizumab in 35 patients with recurrent, surgically resectable glioblastoma. Patients who were randomized to receive neoadjuvant pembrolizumab, with continued adjuvant therapy following surgery, had significantly extended overall survival compared to patients that were randomized to receive adjuvant, post-surgical programmed cell death protein 1 (PD-1) blockade alone. Neoadjuvant PD-1 blockade was associated with upregulation of T cell- and interferon-γ-related gene expression, but downregulation of cell-cycle-related gene expression within the tumor, which was not seen in patients that received adjuvant therapy alone. Focal induction of programmed death-ligand 1 in the tumor microenvironment, enhanced clonal expansion of T cells, decreased PD-1 expression on peripheral blood T cells and a decreasing monocytic population was observed more frequently in the neoadjuvant group than in patients treated only in the adjuvant setting. These findings suggest that the neoadjuvant administration of PD-1 blockade enhances both the local and systemic antitumor immune response and may represent a more efficacious approach to the treatment of this uniformly lethal brain tumor.

https://escholarship.org/content/qt7gf847t7/qt7gf847t7.pdf?t=qaejdd

Neoadjuvant anti-PD-1 immunotherapy promotes a survival benefit with intratumoral and systemic immune responses in recurrent glioblastoma.

Summary Radiotherapy is a critical and inseparable component of comprehensive cancer treatment and care. For many of the most common cancers in low-income and middle-income countries, radiotherapy is essential for effective treatment. In high-income countries, radiotherapy is used in more than half of all cases of cancer to cure localised disease, palliate symptoms, and control disease in incurable cancers. Yet, in planning and building treatment capacity for cancer, radiotherapy is frequently the last resource to be considered. Consequently, worldwide access to radiotherapy is unacceptably low. We present a new body of evidence that quantifies the worldwide coverage of radiotherapy services by country. We show the shortfall in access to radiotherapy by country and globally for 2015–35 based on current and projected need, and show substantial health and economic benefits to investing in radiotherapy. The cost of scaling up radiotherapy in the nominal model in 2015–35 is US$26·6 billion in low-income countries, $62·6 billion in lower-middle-income countries, and $94·8 billion in upper-middle-income countries, which amounts to $184·0 billion across all low-income and middle-income countries. In the efficiency model the costs were lower: $14·1 billion in low-income, $33·3 billion in lower-middle-income, and $49·4 billion in upper-middle-income countries—a total of $96·8 billion. Scale-up of radiotherapy capacity in 2015–35 from current levels could lead to saving of 26·9 million life-years in low-income and middle-income countries over the lifetime of the patients who received treatment. The economic benefits of investment in radiotherapy are very substantial. Using the nominal cost model could produce a net benefit of $278·1 billion in 2015–35 ($265·2 million in low-income countries, $38·5 billion in lower-middle-income countries, and $239·3 billion in upper-middle-income countries). Investment in the efficiency model would produce in the same period an even greater total benefit of $365·4 billion ($12·8 billion in low-income countries, $67·7 billion in lower-middle-income countries, and $284·7 billion in upper-middle-income countries). The returns, by the human-capital approach, are projected to be less with the nominal cost model, amounting to $16·9 billion in 2015–35 (–$14·9 billion in low-income countries; –$18·7 billion in lower-middle-income countries, and $50·5 billion in upper-middle-income countries). The returns with the efficiency model were projected to be greater, however, amounting to $104·2 billion (–$2·4 billion in low-income countries, $10·7 billion in lower-middle-income countries, and $95·9 billion in upper-middle-income countries). Our results provide compelling evidence that investment in radiotherapy not only enables treatment of large numbers of cancer cases to save lives, but also brings positive economic benefits.

https://www.thelancet.com/pdfs/journals/lanonc/PIIS1470-2045(15)00222-3.pdf

Expanding global access to radiotherapy

http://static.guim.co.uk/ni/1432986420413/Ann-Oncol-2015.pdf

A standardised, generic, validated approach to stratify the magnitude of clinical benefit that can be anticipated from anti-cancer therapies: the European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS)

Global colorectal cancer burden in 2020 and projections to 2040

www.thelancet.com/oncology Published online October 27, 2016 http://dx.doi.org/10.1016/S1470-2045(16)30555-1 1 Findings from a population-based cohort study have shown that glucagon-like peptide-1 (GLP-1) analogues for treatment of type 2 diabetes are not associated with an increased incidence of breast cancer. Blánaid M Hicks (Jewish General Hospital, Montreal, QC, Canada) and colleagues examined the records of 44 984 women who were newly treated with glucose-lowering drugs from Jan 1, 2007, to March 31, 2015. The women were drawn from Clinical Practice Research Datalink, a UK database, and were all aged 40 years or older. Mean follow-up was 3·5 years (SD 2·2). 2473 (5·5%) women were prescribed GLP-1 analogues, and 8848 (19·7%) were prescribed dipeptidylpeptidase-4 (DPP-4) inhibitors during the study period. Compared with DPP-4 inhibitors, GLP-1 analogues did not increase the incidence of breast cancer (hazard ratio 1·40 [95% CI 0·91–2·16]). Women using GLP-1 analogues for 2–3 years have an increased incidence of breast cancer (hazard ratio 2·66 [95% CI 1·32–5·38]) compared with those who took the drug for a diff erent amount of time (1·21 [0·64–2·30] for ≤1 year of use, 1·18 [0·59–2·38] for 1·1–2 years of use, and 0·98 [0·24–4·03] for >3 years of use). “A likely explanation is detection bias”, explained senior author Laurent Azoulay (McGill University, Montreal, QC, Canada). But he added that a tumour promoter eff ect could not be ruled out. Lorraine Lipscombe (University of Toronto, ON, Canada) noted that the study did not show a dose–response eff ect. “Normally if a drug increases the risk of cancer, then the longer patients are on the drug, the higher the risk”, she explained. “Here, the risk peaked early and then dropped off —that tells me there must be something else going on.” Anna Morris from Diabetes UK (London, UK) agreed. “There is absolutely nothing in this paper that would suggest that people should stop taking these medications”, she told The Lancet Oncology. Obesity is a risk factor for both type 2 diabetes and breast cancer. It has been suggested that the weight loss associated with GLP-1 analogue use can lead to improved detection of breast lumps. “It was not possible to evaluate the eff ect of rapid weight loss on the detection of breast cancer in this study”, said Azoulay. “It would be of interest to look at this using data from recent large randomised controlled trials of GLP-1 analogues, where bodyweight was measured before randomisation and during follow-up.”

Talha Khan Burki

Papers

Incidence of breast cancer in women with type 2 diabetes

Intensified treatment for IKZF1-deleted childhood leukaemia.

Cancer incidence in Canadian prisoners.

Use of cancer-related emergency departments.

Cancer mortality in Northern Ireland