Showing papers in "British Journal of Cancer in 2017"
TL;DR: The roles tumour-associated macrophages (TAMs) play in regulating different steps of tumour progression and metastasis, and the opportunities to target them in the quest for cancer prevention and treatment are discussed.
Abstract: Macrophages are conventionally classified into M1 and M2 subtypes according to their differentiation status and functional role in the immune system. However, accumulating evidence suggests that this binary classification system is insufficient to account for the remarkable plasticity of macrophages that gives rise to an immense diversity of subtypes. This diverse spectrum of macrophage subtypes play critical roles in various homeostatic and immune functions, but remain far from being fully characterised. In addition to their roles in normal physiological conditions, macrophages also play crucial roles in disease conditions such as cancer. In this review, we discuss the roles tumour-associated macrophages (TAMs) play in regulating different steps of tumour progression and metastasis, and the opportunities to target them in the quest for cancer prevention and treatment.
420 citations
TL;DR: An overview of the immune infiltrate and its spatial organisation is presented, and the prognostic value of immune cells in different cancer types is summarised.
Abstract: Interactions between immune and malignant cells have been known to have clinical relevance for decades. The potential for immune control is now being therapeutically enhanced with checkpoint inhibitors and other novel agents to improve outcomes in cancer. The importance of the immune infiltrate as a prognostic marker is increasingly relevant. In this minireview, we present an overview of the immune infiltrate and its spatial organisation, and summarise the prognostic value of immune cells in different cancer types. International collaborative efforts are standardising histopathologic reporting of the immune infiltrate, to allow application of these parameters in the clinical and research settings. In general terms, a ‘pro-inflammatory’ tumour microenvironment and infiltrating CD8-expressing T lymphocytes are associated with improved clinical outcomes in a broad range of tumour types. The inhibitory function of other immune cells, for example, myeloid-derived suppressor cells and regulatory T cells, appear to have a major role in disrupting the capacity for the immune control of cancers.
297 citations
TL;DR: The historical understanding of one-carbon metabolism in cancer is summarized, the recent findings regarding the generation and usage ofOne-carbon units are described and possible future therapeutics that could exploit the dependency of cancer cells on one- carbon metabolism are explored.
Abstract: Cells require one-carbon units for nucleotide synthesis, methylation and reductive metabolism, and these pathways support the high proliferative rate of cancer cells. As such, anti-folates, drugs that target one-carbon metabolism, have long been used in the treatment of cancer. Amino acids, such as serine are a major one-carbon source, and cancer cells are particularly susceptible to deprivation of one-carbon units by serine restriction or inhibition of de novo serine synthesis. Recent work has also begun to decipher the specific pathways and sub-cellular compartments that are important for one-carbon metabolism in cancer cells. In this review we summarise the historical understanding of one-carbon metabolism in cancer, describe the recent findings regarding the generation and usage of one-carbon units and explore possible future therapeutics that could exploit the dependency of cancer cells on one-carbon metabolism.
287 citations
TL;DR: The role of bystander killing by ADCs is examined and the emerging evidence of how this can occur independently of internalisation is explored.
Abstract: Antibody drug conjugates (ADCs) employ the exquisite specificity of tumour-specific monoclonal antibodies (mAb) for the targeted delivery of highly potent cytotoxic drugs to the tumour site. The chemistry of the linker, which connects the drug to the mAb, determines how and when the drug is released from the mAb. This, as well as the chemistry of the drug, can dictate whether the drug can diffuse into surrounding cells, resulting in 'bystander killing'. Initially, any bystander killing mechanism of action of an ADC was understood to involve an essential sequence of steps beginning with surface antigen targeting, internalisation, intracellular linker cleavage, drug release, and diffusion of drug away from the targeted cell. However, recent studies indicate that, depending on the linker and drug combination, this mechanism may not be essential and ADCs can be cleaved extracellularly or via other mechanisms. In this minireview, we will examine the role of bystander killing by ADCs and explore the emerging evidence of how this can occur independently of internalisation.
236 citations
TL;DR: Evidence suggests that AXL overexpression drives wide-ranging processes, including epithelial to mesenchymal transition, tumour angiogenesis, resistance to chemotherapeutic and targeted agents, and decreased antitumor immune response.
Abstract: The receptor tyrosine kinase AXL, activated by a complex interaction between its ligand growth arrest-specific protein 6 and phosphatidylserine, regulates various vital cellular processes, including proliferation, survival, motility, and immunologic response. Although not implicated as an oncogenic driver itself, AXL, a member of the TYRO3, AXL, and MERTK family of receptor tyrosine kinases, is overexpressed in several haematologic and solid malignancies, including acute myeloid leukaemia, non-small cell lung cancer, gastric and colorectal adenocarcinomas, and breast and prostate cancers. In the context of malignancy, evidence suggests that AXL overexpression drives wide-ranging processes, including epithelial to mesenchymal transition, tumour angiogenesis, resistance to chemotherapeutic and targeted agents, and decreased antitumor immune response. As a result, AXL is an attractive candidate not only as a prognostic biomarker in malignancy but also as a target for anticancer therapies. Several AXL inhibitors are currently in preclinical and clinical development. This article reviews the structure, regulation, and function of AXL; the role of AXL in the tumour microenvironment; the development of AXL as a therapeutic target; and areas of ongoing and future investigation.
212 citations
TL;DR: A novel role of exosomes in mediating the acquired chemoresistance of PC cells is established and either the functional suppression of miR-155 or restoration of DCK led to marked abrogation of Gem-Exo-mediatedChemoresistance.
Abstract: Exosomes confer chemoresistance to pancreatic cancer cells by promoting ROS detoxification and miR-155-mediated suppression of key gemcitabine-metabolising enzyme, DCK
191 citations
TL;DR: Hsa_circ_0000096 may be used as a potential novel biomarker for gastric cancer by regulating cyclin D1, cyclin-dependent kinase 6 (CDK6), matrix metalloproteinase-2 and MMP-9 in vitro and in vivo.
Abstract: Circular RNAs (circRNAs) are a class of non-coding RNAs broadly expressed in cells of various species. Their role in cancers, especially in gastric cancer, is poorly understood. Circular RNA 0000096 (hsa_circ_0000096) levels in 101 paired gastric cancer tissues and adjacent non-tumorous tissues from patients with gastric cancer were detected by real-time quantitative reverse transcription-polymerase chain reaction. A receiver operating characteristic curve was generated to evaluate the diagnostic value of hsa_circ_0000096. RNA interference was used to manipulate the expression of hsa_circ_0000096. Its biological effects were evaluated by flow cytometry, real-time cell analysis, a wound scratch assay, western blot analysis and xenograft models. Hsa_circ_0000096 was found to be significantly downregulated in gastric cancer tissues and gastric cancer cell lines compared with paired adjacent non-tumorous tissues and normal gastric epithelial cells (P<0.001). Moreover, knockdown of hsa_circ_0000096 significantly inhibited cell proliferation and migration in vitro and in vivo. The results of both immunohistochemical and western blot analyses showed that the protein levels of cyclin D1, cyclin-dependent kinase 6 (CDK6), matrix metalloproteinase-2 and MMP-9 were significantly reduced in vitro and in vivo. A gastric cancer xenograft nude mouse model indicated that Ki67 and VEGF were reduced in a dose-dependent manner following knockdown of hsa_circ_0000096. However, the expression of E-cadherin increased. Hsa_circ_0000096 may be used as a potential novel biomarker for gastric cancer. It affects gastric cancer cell growth and migration by regulating cyclin D1, CDK6, MMP-2 and MMP-9.
188 citations
TL;DR: The foundation for pillars and hallmarks of response to immune checkpoint blockade are described, with a discussion of their relevance to immune monitoring and mechanisms of resistance.
Abstract: Unprecedented advances have been made in the treatment of cancer through the use of immune checkpoint blockade, with approval of several checkpoint blockade regimens spanning multiple cancer types However, responses to this form of therapy are not universal, and insights are clearly needed to identify optimal biomarkers of response and to combat mechanisms of therapeutic resistance A working knowledge of the hallmarks of cancer yields insight into responses to immune checkpoint blockade, although the focus of this is rather tumour-centric and additional factors are pertinent, including host immunity and environmental influences Herein, we describe the foundation for pillars and hallmarks of response to immune checkpoint blockade, with a discussion of their relevance to immune monitoring and mechanisms of resistance Evolution of this understanding will ultimately help guide treatment strategies to enhance therapeutic responses
182 citations
Erasmus University Rotterdam1, University of Copenhagen2, Institute of Cancer Research3, McGill University Health Centre4, McGill University5, Vrije Universiteit Brussel6, Royal Hallamshire Hospital7, Sheba Medical Center8, Umeå University9, University of Sheffield10, University of Valencia11, AstraZeneca12
TL;DR: The current guidelines allow for reproducible determination of liver metastasis HGPs and may serve as a novel biomarker for individualised therapies for CRCLM patients.
Abstract: Liver metastases present with distinct histopathological growth patterns (HGPs), including the desmoplastic, pushing and replacement HGPs and two rarer HGPs. The HGPs are defined owing to the distinct interface between the cancer cells and the adjacent normal liver parenchyma that is present in each pattern and can be scored from standard haematoxylin-and-eosin-stained (H&E) tissue sections. The current study provides consensus guidelines for scoring these HGPs. Guidelines for defining the HGPs were established by a large international team. To assess the validity of these guidelines, 12 independent observers scored a set of 159 liver metastases and interobserver variability was measured. In an independent cohort of 374 patients with colorectal liver metastases (CRCLM), the impact of HGPs on overall survival after hepatectomy was determined. Good-to-excellent correlations (intraclass correlation coefficient >0.5) with the gold standard were obtained for the assessment of the replacement HGP and desmoplastic HGP. Overall survival was significantly superior in the desmoplastic HGP subgroup compared with the replacement or pushing HGP subgroup (P=0.006). The current guidelines allow for reproducible determination of liver metastasis HGPs. As HGPs impact overall survival after surgery for CRCLM, they may serve as a novel biomarker for individualised therapies.
160 citations
TL;DR: Subcutaneous adipose tissues appear to associate with reduction in mortality risk demonstrating the prognostic importance ofFat distribution, and the effect of sarcopenia on survival was more pronounced in patients with low subcutaneous obesity.
Abstract: Prognostic significance of adiposity, at the time of cancer diagnosis, on survival is not clear. Body mass index (kg m−2) does not provide an appropriate assessment of body composition; therefore, the concept of the ‘obesity paradox’ needs to be investigated based on the prognostic significance of fat and muscle. Independent prognostic significance of adipose tissue in predicting mortality, importance of visceral and subcutaneous adiposity in the presence and absence of sarcopenia on survival, was investigated. Adiposity markers including total adipose index (TATI), visceral adipose tissue index (VATI) and subcutaneous adipose tissue index (SATI) were estimated for 1473 gastrointestinal and respiratory cancer patients and 273 metastatic renal cell carcinoma patients using computed tomography. Univariate and multivariate analysis to determine mortality hazard ratios (HR) were conducted using cox proportional hazard models. Low SATI (SATI <50.0 cm2 m−2 in males and <42.0 cm2 m−2 in females) independently associated with increased mortality (HR: 1.26; 95% CI: 1.11–1.43; P<0.001) and shorter survival (13.1 months; 95% CI, 11.4–14.7) compared to patients with high SATI (19.3 months; 95% CI, 17.6–21.0; P<0.001). In the presence of sarcopenia, the longest survival was observed in patients with high subcutaneous adiposity. Subcutaneous adipose tissues appear to associate with reduction in mortality risk demonstrating the prognostic importance of fat distribution. The effect of sarcopenia on survival was more pronounced in patients with low subcutaneous adiposity.
152 citations
TL;DR: Research on routinely available blood and clinical markers has focussed primarily on ICI use in melanoma, the use of ipilimumab and on univariate associations, but preliminary evidence is emerging for other cancer types, other ICIs and for combining markers in multivariable clinical prediction models.
Abstract: Immune checkpoint inhibitors (ICI) are an important development in the treatment of advanced cancer. A substantial proportion of patients treated with ICI do not respond, and additionally patients discontinue treatment due to adverse effects. While many novel biological markers related to the specific mechanisms of ICI actions have been investigated, there has also been considerable research to identify routinely available blood and clinical markers that may predict response to ICI therapy. If validated, these markers have the advantage of being easily integrated into clinical use for nominal expense. Several markers have shown promise, including baseline and post-treatment changes in leucocyte counts, lactate dehydrogenase and C-reactive protein. While promising, the results between studies have been inconsistent due to small sample sizes, follow-up time and variability in the assessed markers. To date, research on routinely available blood and clinical markers has focussed primarily on ICI use in melanoma, the use of ipilimumab and on univariate associations, but preliminary evidence is emerging for other cancer types, other ICIs and for combining markers in multivariable clinical prediction models.
TL;DR: Elotinib was not significantly superior to gefitinib in terms of efficacy in advanced non-small cell lung cancer with epidermal growth factor receptor mutations in exon 19 or 21, and the two treatments had similar toxicities.
Abstract: A phase III trial was conducted to compare the safety and efficacy of erlotinib with that of gefitinib in advanced non-small cell lung cancer harbouring epidermal growth factor receptor mutations in exon 19 or 21. Eligible patients were randomised to receive erlotinib (150 mg per day) or gefitinib (250 mg per day) orally until disease progression or unacceptable toxicity. We aimed to determine whether erlotinib is superior to gefitinib in efficacy. The primary end point was progression-free survival. A total of 256 patients were randomised to receive erlotinib (N=128) or gefitinib (N=128). Median progression-free survival was not better with erlotinib than with gefitinib (13.0 vs 10.4 months, 95% confidence interval (CI) 0.62–1.05, P=0.108). The corresponding response rates and median overall survival were 56.3% vs 52.3% (P=0.530) and 22.9 vs 20.1 months (95% CI 0.63–1.13, P=0.250), respectively. There were no significant differences in grade 3/4 toxicities between the two arms (P=0.172). The primary end point was not met. Erlotinib was not significantly superior to gefitinib in terms of efficacy in advanced non-small cell lung cancer with epidermal growth factor receptor mutations in exon 19 or 21, and the two treatments had similar toxicities.
TL;DR: There was no sufficient evidence to support p53, Ki-67 and p16 as prognostic biomarkers for OTSCC, but the quality of the conduct and reporting of original studies is overall unsatisfactory which does not allow reliable conclusions.
Abstract: Identifying informative prognostic biomarkers for oral tongue squamous cell carcinoma (OTSCC) is of great importance in order to better predict tumour behaviour and to guide treatment planning. Here, we summarise existing evidence regarding immunohistochemical prognostic biomarkers for OTSCC. A systematic search of the literature was performed using the databases of Scopus, Ovid Medline, Web of Science and Cochrane Library. All studies which had investigated the prognostic significance of immunohistochemical biomarkers in OTSCC during the period from 1985 to 2015 were retrieved. For the five most often evaluated biomarkers a random-effects meta-analysis on overall survival was performed, including those studies that provided the necessary statistical results. A total of 174 studies conducted during the last three decades were found, and in these 184 biomarkers were evaluated for the prognostication of OTSCC. The five biomarkers most frequently assessed were p53, Ki-67, p16, VEGFs and cyclin D1. In the meta-analyses, the most promising results of the prognostic power for OTSCC were obtained for cyclin D1. For studies of VEGF A and C the results were equivocal, but the pooled analysis of VEGF A separately showed it to be a useful prognosticator for OTSCC. There was no sufficient evidence to support p53, Ki-67 and p16 as prognostic biomarkers for OTSCC. Limitations in the quality of the published studies (e.g., small cohorts, lack of compliance with REMARK guidelines) are widespread. Numerous biomarkers have been presented as useful prognosticators for OTSCC, but the quality of the conduct and reporting of original studies is overall unsatisfactory which does not allow reliable conclusions. The value of two biomarkers (VEGF-A and cyclin D1) should be validated in a multicentre study setting following REMARK guidelines.
TL;DR: Patients with sarcopenia and low MA are more likely to experience severe treatment-related toxicity to Ipi, and loss of muscle during treatment was predictive of worse survival.
Abstract: Body composition is an important predictor of drug toxicity and outcome. Ipilimumab (Ipi), a monoclonal antibody used to treat metastatic melanoma, has specific toxicities. No validated biomarkers that predict Ipi toxicity and efficacy exist. Also, the impact of Ipi on body composition has not been established. Patients with metastatic melanoma treated with Ipi between 2009 and 2015 were included. Body composition was assessed by computed tomography at baseline and after four cycles of Ipi. Sarcopenia and low muscle attenuation (MA) were defined using published cut-points. All adverse events (AEs) and immune-related AEs (irAEs) were recorded (Common Terminology Criteria For Adverse Event V.4.0). Eighty-four patients were included in this study (62% male, median age 54 years). At baseline, 24% were sarcopenic and 33% had low MA. On multivariate analysis, sarcopenia and low MA were significantly associated with high-grade AEs (OR=5.34, 95% CI: 1.15–24.88, P=0.033; OR=5.23, 95% CI: 1.41–19.30, P=0.013, respectively), and low MA was associated with high-grade irAEs (OR=3.57, 95% CI: 1.09–11.77, P=0.036). Longitudinal analysis (n=59) revealed significant reductions in skeletal muscle area (SMA), total body fat-free mass, fat mass (all P<0.001) and MA (P=0.030). Mean reduction in SMA was 3.3%/100 days (95% CI: −4.48 to −1.79%, P<0.001). A loss of SMA ⩾7.5%/100 days (highest quartile) was a significant predictor of overall survival in multivariable Cox regression analysis (HR: 2.1, 95% CI: 1.02–4.56, P=0.046). Patients with sarcopenia and low MA are more likely to experience severe treatment-related toxicity to Ipi. Loss of muscle during treatment was predictive of worse survival. Treatments to increase muscle mass and influence outcome warrant further investigation.
TL;DR: The function of tumour-derived ALPL, the gene that encodes for tissue nonspecific ALP, is revealed in regulating cell death and epithelial plasticity, and a strong association between ALPL expression in PCa cells and metastasis or disease-free survival is demonstrated, identified as a major contributor to the pathogenesis of PCa progression.
Abstract: Recent evidence suggests that bone-related parameters are the main prognostic factors for overall survival in advanced prostate cancer (PCa), with elevated circulating levels of alkaline phosphatase (ALP) thought to reflect the dysregulated bone formation accompanying distant metastases. We have identified that PCa cells express ALPL, the gene that encodes for tissue nonspecific ALP, and hypothesised that tumour-derived ALPL may contribute to disease progression. Functional effects of ALPL inhibition were investigated in metastatic PCa cell lines. ALPL gene expression was analysed from published PCa data sets, and correlated with disease-free survival and metastasis. ALPL expression was increased in PCa cells from metastatic sites. A reduction in tumour-derived ALPL expression or ALP activity increased cell death, mesenchymal-to-epithelial transition and reduced migration. Alkaline phosphatase activity was decreased by the EMT repressor Snail. In men with PCa, tumour-derived ALPL correlated with EMT markers, and high ALPL expression was associated with a significant reduction in disease-free survival. Our studies reveal the function of tumour-derived ALPL in regulating cell death and epithelial plasticity, and demonstrate a strong association between ALPL expression in PCa cells and metastasis or disease-free survival, thus identifying tumour-derived ALPL as a major contributor to the pathogenesis of PCa progression.
TL;DR: Most tumour budding signatures were EMT-positive and switched from an epithelial subtype in the tumour bulk to a mesenchymal subtype (CMS4) in budding cells, characterised by a phenotype switch compared with the tumours bulk.
Abstract: Tumour budding, described as the presence of single cells or small clusters of up to five tumour cells at the invasive margin, is established as a prognostic marker in colorectal carcinoma. In the present study, we aimed to investigate the molecular signature of tumour budding cells and the corresponding tumour bulk. Tumour bulk and budding areas were microdissected and processed for RNA-sequencing. As little RNA was obtained from budding cells, a special low-input mRNA library preparation protocol was used. Gene expression profiles of budding as compared with tumour bulk were investigated for established EMT signatures, consensus molecular subtype (CMS), gene set enrichment and pathway analysis. A total of 296 genes were differentially expressed with an FDR <0.05 and a twofold change between tumour bulk and budding regions. Genes that were upregulated in the budding signature were mainly involved in cell migration and survival while downregulated genes were important for cell proliferation. Supervised clustering according to an established EMT gene signature categorised budding regions as EMT-positive, whereas tumour bulk was considered EMT-negative. Furthermore, a shift from CMS2 (epithelial) to CMS4 (mesenchymal) was observed as tumour cells transit from the tumour bulk to the budding regions. Tumour budding regions are characterised by a phenotype switch compared with the tumour bulk, involving the acquisition of migratory characteristics and a decrease in cell proliferation. In particular, most tumour budding signatures were EMT-positive and switched from an epithelial subtype (CMS2) in the tumour bulk to a mesenchymal subtype (CMS4) in budding cells.
TL;DR: Stereotactic body radiotherapy seems to be a useful treatment both for oligorecurrent and oligo-CRPC, with promising results in distant progression-free survival and second-line systemic treatment- free survival.
Abstract: The aim of the present study is to evaluate the impact of metastases-directed stereotactic body radiotherapy in two groups of oligometastatic prostate cancer (PC) patients: oligorecurrent PC and oligoprogressive castration-resistant PC (oligo-CRPC). Inclusion criteria of the present multicentre retrospective analysis were: (1) oligorecurrent PC, defined as the presence of 1–3 lesions (bone or nodes) detected with choline positron emission tomography or CT plus bone scan following biochemical recurrence; (2) oligo-CRPC, defined as metastases (bone or nodes) detected after a prostatic-specific antigen rise during androgen deprivation therapy (ADT). Primary end points were: distant progression-free survival (DPFS) and ADT-free survival in oligorecurrent PC patients; DPFS and second-line systemic treatment-free survival in oligo-CRPC patients. About 100 patients with oligorecurrent PC (139 lesions) and 41 with oligo-CRPC (70 lesions), treated between March 2010 and April 2016, were analysed. After a median follow-up of 20.4 months, in the oligorecurrent group 1- and 2-year DPFS were 64.4 and 43%. The rate of LC was 92.8% at 2 years. At a median follow-up of 23.4 months, in the oligo-CRPC group 1- and 2-year DPFS were 43.2 and 21.6%. Limitations include the retrospective design. Stereotactic body radiotherapy seems to be a useful treatment both for oligorecurrent and oligo-CRPC.
TL;DR: Higher 25OHD concentration is associated with better cancer outcome, and the observed association of functional variants in vitamin D pathway genes with outcome supports a causal link.
Abstract: Vitamin D has been linked with improved cancer outcome. This systematic review and meta-analysis investigates the relationship between cancer outcomes and both vitamin D-related genetic variation and circulating 25-hydroxyvitamin D (25OHD) concentration. A systematic review and meta-analysis of papers until November 2016 on PubMed, EMBASE and Web of Science pertaining to association between circulating vitamin D level, functionally relevant vitamin D receptor genetic variants and variants within vitamin D pathway genes and cancer survival or disease progression was performed. A total of 44 165 cases from 64 studies were included in meta-analyses. Higher 25OHD was associated with better overall survival (hazard ratio (HR=0.74, 95% CI: 0.66–0.82) and progression-free survival (HR=0.84, 95% CI: 0.77–0.91). The rs1544410 (BsmI) variant was associated with overall survival (HR=1.40, 95% CI: 1.05–1.75) and rs7975232 (ApaI) with progression-free survival (HR=1.29, 95% CI: 1.02–1.56). The rs2228570 (FokI) variant was associated with overall survival in lung cancer patients (HR=1.29, 95% CI: 1.0–1.57), with a suggestive association across all cancers (HR=1.26, 95% CI: 0.96–1.56). Higher 25OHD concentration is associated with better cancer outcome, and the observed association of functional variants in vitamin D pathway genes with outcome supports a causal link. This analysis provides powerful background rationale to instigate clinical trials to investigate the potential beneficial effect of vitamin D in the context of stratification by genotype.
TL;DR: The extent of tumour heterogeneity and its effect on the evaluation of a selected prognostic marker using prostate cancer as a model was examined and DNA ploidy was a significant prognostic markers when heterogeneity was taken into consideration.
Abstract: The high degree of genomic diversity in cancer represents a challenge for identifying objective prognostic markers. We aimed to examine the extent of tumour heterogeneity and its effect on the evaluation of a selected prognostic marker using prostate cancer as a model. We assessed Gleason Score (GS), DNA ploidy status and phosphatase and tensin homologue (PTEN) expression in radical prostatectomy specimens (RP) from 304 patients followed for a median of 10 years (interquartile range 6–12). GS was assessed for every tumour-containing block and DNA ploidy for a median of four samples for each RP. In a subgroup of 40 patients we assessed DNA ploidy and PTEN status in every tumour-containing block. In 102 patients assigned to active surveillance (AS), GS and DNA ploidy were studied in needle biopsies. Extensive heterogeneity was observed for GS (89% of the patients) and DNA ploidy (40% of the patients) in the cohort, and DNA ploidy (60% of the patients) and PTEN expression (75% of the patients) in the subgroup. DNA ploidy was a significant prognostic marker when heterogeneity was taken into consideration. In the AS cohort we found heterogeneity in GS (24%) and in DNA ploidy (25%) specimens. Multi-sample analysis should be performed to support clinical treatment decisions.
TL;DR: A panel to use in ultra-deep sequencing to identify mutated alleles in cfDNA involved in non-small-cell lung cancer, gastrointestinal stromal tumour, colorectal carcinoma and melanoma and a feasible NGS panel for cfDNA analysis in clinical practice is developed.
Abstract: Development of a gene panel for next-generation sequencing of clinically relevant mutations in cell-free DNA from cancer patients
TL;DR: The ability of mrTRG to identify pathological complete responders for the adoption of non-operative management strategies and to provide complementary prognostic information to pTRG for better risk-stratification after surgery is found to be low.
Abstract: Limited data exist regarding the correlation between MRI tumour regression grade (mrTRG) and pathological TRG (pTRG) in rectal cancer. mrTRG and pTRG were compared in rectal cancer patients from two phase II trials (EXPERT and EXPERT-C). The agreement between radiologist and pathologist was assessed with the weighted κ test while the Kaplan–Meier method was used to estimate survival outcomes. One hundred ninety-one patients were included. Median time from completion of neoadjuvant treatment to pre-operative MRI and surgery was 4.1 weeks (interquartile range (IQR): 3.7–4.7) and 6.6 weeks (IQR: 5.9–7.6), respectively. Fair agreement was found between mrTRG and pTRG when regression was classified according to standard five-tier systems (κ=0.24) or modified three-tier systems (κ=0.25). Sensitivity and specificity of mrTRG 1–2 (complete/good radiological regression) for the prediction of pathological complete response was 74.4% (95% CI: 58.8–86.5) and 62.8% (95% CI: 54.5–70.6), respectively. Survival outcomes of patients with intermediate pathological regression (pTRG 2) were numerically better if complete/good regression was also observed on imaging (mrTRG 1–2) compared to poor regression (mrTRG 3–5) (5-year recurrence-free survival 76.9% vs 65.9%, P=0.18; 5-year overall survival 80.6% vs 68.8%, P=0.22). The agreement between mrTRG and pTRG is low and mrTRG cannot be used as a surrogate of pTRG. Further studies are warranted to assess the ability of mrTRG to identify pathological complete responders for the adoption of non-operative management strategies and to provide complementary prognostic information to pTRG for better risk-stratification after surgery.
TL;DR: Systematic assessment of geriatric domains is needed to aid oncologists in identifying frail patients with poor survival in older cancer patients.
Abstract: Frailty is a syndrome associated with increased vulnerability and an important predictor of outcomes in older cancer patients. Systematic assessments to identify frailty are seldom applied, and oncologists’ ability to identify frailty is scarcely investigated. We compared oncologists’ classification of frailty (onc-frail) based on clinical judgement with a modified geriatric assessment (mGA), and investigated associations between frailty and overall survival. Patients ⩾70 years referred for medical cancer treatment were eligible. mGA-frailty was defined as impairment in at least one of the following: daily activities, comorbidity, polypharmacy, physical function or at least one geriatric syndrome (cognitive impairment, depression, malnutrition, falls). Three hundred and seven patients were enroled, 288 (94%) completed the mGA, 286 (93%) were rated by oncologists. Median age was 77 years, 56% had metastases, 85% performance status (PS) 0–1. Overall, 104/286 (36%) were onc-frail and 140/288 (49%) mGA-frail, the agreement was fair (kappa value 0.30 (95% CI 0.19; 0.41)), and 67 mGA-frail patients who frequently had localised disease, good PS and received curative treatment, were missed by the oncologists. Only mGA-frailty was independently prognostic for survival (HR 1.61, 95% CI 1.14; 2.27; P=0.007). Systematic assessment of geriatric domains is needed to aid oncologists in identifying frail patients with poor survival.
TL;DR: The development of a highly specific and sensitive ELISA for the capture of PS-expressing tumour exosomes in the blood of tumour-bearing mice indicates that blood PS exosome levels is a specific indicator of cancer and suggests that bloodPS is a biomarker for early-stage malignancies.
Abstract: Detection of phosphatidylserine-positive exosomes for the diagnosis of early-stage malignancies
TL;DR: Standard dose P can be safely combined with G, G+NP, G+, G+V, I and LD and evaluation to determine if response and duration of response are more robust than what would be expected for chemotherapy or immunotherapy alone requires further validation.
Abstract: Pembrolizumab (P) is an anti-PD-1 antibody that blocks the interaction between programmed cell death protein 1 (PD-1) on T-cells and PD-L1 and PD-L2 on tumour cells. A phase Ib trial of P plus chemotherapy was undertaken to evaluate the safety and efficacy. Patients with advanced, metastatic solid tumours were enrolled onto one of six treatment arms. Pembrolizumab was given: with gemcitabine (G), G+docetaxel (D), G+nab-paclitaxel (NP), G+vinorelbine (V) or irinotecan (I) until progression or toxicity, or with liposomal doxorubicin (LD) for up to 15 cycles, progression or toxicity. Safety monitoring and response assessments were conducted. Forty-nine patients were enrolled and treated. The most common adverse events were transaminitis, cytopenias, rash, diarrhoea, fatigue, nausea and vomiting. Arm 2 was closed due to poor accrual. The recommended phase II dose (RP2D) was determined for Arms 1, 3a, 4, 5 and 6. There were eight partial responses across multiple tumour types. Standard dose P can be safely combined with G, G+NP, G+V, I and LD. Efficacy was observed in multiple tumour types and evaluation to determine if response and duration of response are more robust than what would be expected for chemotherapy or immunotherapy alone requires further validation.
TL;DR: Mutation analysis of plasma-derived cfDNA by ddPCR suggests that PFS benefit of everolimus was maintained irrespective of PIK3CA genotypes, consistent with the previous analysis of archival tumour DNA by next-generation sequencing.
Abstract: Correlation between PIK3CA mutations in cell-free DNA and everolimus efficacy in HR + , HER2 − advanced breast cancer: results from BOLERO-2
TL;DR: For patients with colorectal cancer, pG12C and p.G12V mutations in codon 12 were independently associated with worse overall survival after diagnosis, and were predictive of overall survival.
Abstract: Activating mutations in KRAS have been suggested as potential predictive and prognostic biomarkers. However, the prognostic impact of specific point mutations remains less clear. This study assessed the prognostic impact of specific KRAS mutations on survival for patients with colorectal cancer. Retrospective review of patients KRAS typed for advanced and recurrent colorectal cancer between 2010 and 2015 in a UK Cancer Network. We evaluated the impact of KRAS genotype in 392 patients. Mutated KRAS was detected in 42.9% of tumours. KRAS mutations were more common in moderate vs well-differentiated tumours. On multivariate analysis, primary tumour T stage (HR 2.77 (1.54–4.98), P=0.001), N stage (HR 1.51 (1.01–2.26), P=0.04), curative intent surgery (HR 0.51 (0.34–0.76), P=0.001), tumour grade (HR 0.44 (0.30–0.65), P=0.001) and KRAS mutation (1.54 (1.23–2.12), P=0.005) were all predictive of overall survival. Patients with KRAS codon 12 mutations had worse overall survival (HR 1.76 (95% CI 1.27–2.43), P=0.001). Among the five most common codon 12 mutations, only p.G12C (HR 2.21 (1.15–4.25), P=0.01) and p.G12V (HR 1.69 (1.08–2.62), P=0.02) were predictive of overall survival. For patients with colorectal cancer, p.G12C and p.G12V mutations in codon 12 were independently associated with worse overall survival after diagnosis.
TL;DR: Based on a large cohort of patients, a simple five-factor prediction scale for the clinical activity of PD-1 antibodies in advanced melanoma patients is developed and validated and can be used to stratify patients participating in clinical trials.
Abstract: Anti-PD-1 therapy has shown significant clinical activity in advanced melanoma. We developed and validated a clinical prediction scale for response to anti- PD-1 monotherapy. A total of 315 patients with advanced melanoma treated with pembrolizumab (2 or 10 mg kg−1 Q2W or Q3W) or nivolumab (3 mg kg−1 Q2W) at four cancer centres between 2011 to 2013 served as the setting for the present cohort study. Variables with significant association to response on a univariate analysis were entered into a forward stepwise logistic regression model and were given a score based on ORs to calculate a clinical prediction scale. The developed clinical prediction scale included elevated LDH (1 point), age <65 years (1 point), female sex (1 point), history of ipilimumab treatment (2 points) and the presence of liver metastasis (2 points). The scale had an area under the receiver-operating curve (AUC) of 0.73 (95% CI 0.67, 0.80) in predicting response to therapy. The predictive performance of the score was maintained in the validation cohort (AUC 0.70 (95% CI 0.58, 0.81)) and the goodness-to-fit model demonstrated good calibration. Based on a large cohort of patients, we developed and validated a simple five-factor prediction scale for the clinical activity of PD-1 antibodies in advanced melanoma patients. This scale can be used to stratify patients participating in clinical trials.
TL;DR: Although CNA are frequent events in microsatellite stable CRC, few focal recurrent regions were found and these aberrations have strong effects on gene expression and contribute to deregulate relevant cancer pathways.
Abstract: Somatic copy number aberrations (CNAs) are common acquired changes in cancer cells having an important role in the progression of colon cancer (colorectal cancer, CRC). This study aimed to perform a characterisation of CNA and their impact in gene expression. Copy number aberrations were inferred from SNP array data in a series of 99 CRC. Copy number aberration events were calculated and used to assess the association between copy number dosage, clinical and molecular characteristics of the tumours, and gene expression changes. All analyses were adjusted for the quantity of stroma in each sample, which was inferred from gene expression data. High heterogeneity among samples was observed; the proportion of altered genome ranged between 0.04 and 26.6%. Recurrent CNA regions with gains were frequent in chromosomes 7p, 8q, 13q, and 20, whereas 8p, 17p, and 18 cumulated losses. A significant positive correlation was observed between the number of somatic mutations and total CNA (Spearman’s r=0.42, P=0.006). Approximately 37% of genes located in CNA regions changed their level of expression and the average partial correlation (adjusted for stromal content) with copy number was 0.54 (interquartile range 0.20 to 0.81). Altered genes showed enrichment in pathways relevant for CRC. Tumours classified as CMS2 and CMS4 by the consensus molecular subtyping showed higher frequency of CNA. Losses of one small region in 1p36.33, with gene CDK11B, were associated with poor prognosis. More than 66% of the recurrent CNA were validated in the The Cancer Genome Atlas (TCGA) data when analysed with the same procedure. Furthermore, 79% of the genes with altered expression in our data were validated in the TCGA. Although CNA are frequent events in microsatellite stable CRC, few focal recurrent regions were found. These aberrations have strong effects on gene expression and contribute to deregulate relevant cancer pathways. Owing to the diploid nature of stromal cells, it is important to consider the purity of tumour samples to accurately calculate CNA events in CRC.
TL;DR: MRI-detected extramural vascular invasion is prevalent in one-third of patients with rectal cancer and a poor prognostic factor as evidenced by the five-fold increased rate of synchronous metastases, and almost four-fold ongoing risk of developing metastases in follow-up after surgery.
Abstract: Pathological extramural vascular invasion (EMVI) is an independent prognostic factor in rectal cancer, but can also be identified on MRI-detected extramural vascular invasion (mrEMVI). We perform a meta-analysis to determine the risk of metastatic disease at presentation and after surgery in mrEMVI-positive patients compared with negative tumours. Electronic databases were searched from January 1980 to March 2016. Conventional meta-analytical techniques were used to provide a summative outcome. Quality assessment of the studies was performed. Six articles reported on mrEMVI in 1262 patients. There were 403 patients in the mrEMVI-positive group and 859 patients in the mrEMVI-negative group. The combined prevalence of mrEMVI-positive tumours was 0.346(range=0.198–0.574). Patients with mrEMVI-positive tumours presented more frequently with metastases compared to mrEMVI-negative tumours (fixed effects model: odds ratio (OR)=5.68, 95% confidence interval (CI) (3.75, 8.61), z=8.21, df=2, P<0.001). Patients who were mrEMVI-positive developed metastases more frequently during follow-up (random effects model: OR=3.91, 95% CI (2.61, 5.86), z=6.63, df=5, P<0.001). MRI-detected extramural vascular invasion is prevalent in one-third of patients with rectal cancer. MRI-detected extramural vascular invasion is a poor prognostic factor as evidenced by the five-fold increased rate of synchronous metastases, and almost four-fold ongoing risk of developing metastases in follow-up after surgery.
TL;DR: Evidence from the recent literature is highlighted to discuss how conditions within the tumour microenvironment shape the metabolic character of tumours.
Abstract: Cancer cells exhibit metabolic alterations that distinguish them from healthy tissues and make their metabolic processes susceptible to pharmacological targeting. Although typical cell-autonomous features of cancer metabolism have been emerging, it is increasingly appreciated that extrinsic factors also influence the metabolic properties of tumours. This review highlights evidence from the recent literature to discuss how conditions within the tumour microenvironment shape the metabolic character of tumours.