Publications by authors named "Cheryl Gillett"

66 Publications

Hypoxia-sensing CAR T cells provide safety and efficacy in treating solid tumors.

Cell Rep Med 2021 Apr 9;2(4):100227. Epub 2021 Apr 9.

School of Cancer and Pharmaceutical Sciences, King's College London, Faculty of Life Sciences and Medicine, Guy's Campus, London SE1 1UL, UK.

Utilizing T cells expressing chimeric antigen receptors (CARs) to identify and attack solid tumors has proven challenging, in large part because of the lack of tumor-specific targets to direct CAR binding. Tumor selectivity is crucial because on-target, off-tumor activation of CAR T cells can result in potentially lethal toxicities. This study presents a stringent hypoxia-sensing CAR T cell system that achieves selective expression of a pan-ErbB-targeted CAR within a solid tumor, a microenvironment characterized by inadequate oxygen supply. Using murine xenograft models, we demonstrate that, despite widespread expression of ErbB receptors in healthy organs, the approach provides anti-tumor efficacy without off-tumor toxicity. This dynamic on/off oxygen-sensing safety switch has the potential to facilitate unlimited expansion of the CAR T cell target repertoire for treating solid malignancies.
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http://dx.doi.org/10.1016/j.xcrm.2021.100227DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8080111PMC
April 2021

Proteomics of REPLICANT perfusate detects changes in the metastatic lymph node microenvironment.

NPJ Breast Cancer 2021 Mar 5;7(1):24. Epub 2021 Mar 5.

The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK.

In breast cancer (BC), detecting low volumes of axillary lymph node (ALN) metastasis pre-operatively is difficult and novel biomarkers are needed. We recently showed that patient-derived ALNs can be sustained ex-vivo using normothermic perfusion. We now compare reactive (tumour-free; n = 5) and macrometastatic (containing tumour deposits >2 mm; n = 4) ALNs by combining whole section multiplex immunofluorescence with TMT-labelled LC-MS/MS of the circulating perfusate. Macrometastases contained significantly fewer B cells and T cells (CD4/CD8/regulatory) than reactive nodes (p = 0.02). Similarly, pathway analysis of the perfusate proteome (119/1453 proteins significantly differentially expressed) showed that immune function was diminished in macrometastases in favour of 'extracellular matrix degradation'; only 'neutrophil degranulation' was preserved. Qualitative comparison of the perfusate proteome to that of node-positive pancreatic and prostatic adenocarcinoma also highlighted 'neutrophil degranulation' as a contributing factor to nodal metastasis. Thus, metastasis-induced changes in the REPLICANT perfusate proteome are detectable, and could facilitate biomarker discovery.
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http://dx.doi.org/10.1038/s41523-021-00227-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7935848PMC
March 2021

Cancer-associated hypersialylated MUC1 drives the differentiation of human monocytes into macrophages with a pathogenic phenotype.

Commun Biol 2020 Nov 4;3(1):644. Epub 2020 Nov 4.

Breast Cancer Biology, Comprehensive Cancer Centre, King's College London, Guy's Cancer Centre, Guy's Hospital, London, SE1 9RT, UK.

The tumour microenvironment plays a crucial role in the growth and progression of cancer, and the presence of tumour-associated macrophages (TAMs) is associated with poor prognosis. Recent studies have demonstrated that TAMs display transcriptomic, phenotypic, functional and geographical diversity. Here we show that a sialylated tumour-associated glycoform of the mucin MUC1, MUC1-ST, through the engagement of Siglec-9 can specifically and independently induce the differentiation of monocytes into TAMs with a unique phenotype that to the best of our knowledge has not previously been described. These TAMs can recruit and prolong the lifespan of neutrophils, inhibit the function of T cells, degrade basement membrane allowing for invasion, are inefficient at phagocytosis, and can induce plasma clotting. This macrophage phenotype is enriched in the stroma at the edge of breast cancer nests and their presence is associated with poor prognosis in breast cancer patients.
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http://dx.doi.org/10.1038/s42003-020-01359-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7642421PMC
November 2020

Cohort profile: King's Health Partners bladder cancer biobank.

BMC Cancer 2020 Sep 25;20(1):920. Epub 2020 Sep 25.

Translational Oncology & Urology Research (TOUR), School of Cancer and Pharmaceutical Sciences, King's College London, Guy's Hospital, 3rd Floor Bermondsey Wing, London, SE1 9RT, UK.

Background: Bladder cancer (BC) is the 9th most common cancer worldwide, but little progress has been made in improving patient outcomes over the last 25 years. The King's Health Partners (KHP) BC biobank was established to study unanswered, clinically relevant BC research questions. Donors are recruited from the Urology or Oncology departments of Guy's Hospital (UK) and can be approached for consent at any point during their treatment pathway. At present, patients with bladder cancer are approached to provide their consent to provide blood, urine and bladder tissue. They also give access to medical records and linkage of relevant clinical and pathological data across the course of their disease. Between June 2017 and June 2019, 531 out of 997 BC patients (53.3%) gave consent to donate samples and data to the Biobank. During this period, the Biobank collected fresh frozen tumour samples from 90/178 surgical procedures (of which 73 were biopsies) and had access to fixed, paraffin embedded samples from all patients who gave consent. Blood and urine samples have been collected from 38 patients, all of which were processed into component derivatives within 1 to 2 h of collection. This equates to 193 peripheral blood mononuclear cell vials; 238 plasma vials, 224 serum vials, 414 urine supernatant vials and 104 urine cell pellets. This biobank population is demographically and clinically representative of the KHP catchment area.

Conclusion: The King's Health Partners BC Biobank has assembled a rich data and tissue repository which is clinically and demographically representative of the local South East London BC population, making it a valuable resource for future BC research.
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http://dx.doi.org/10.1186/s12885-020-07437-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7519499PMC
September 2020

Invasive breast cancer over four decades reveals persisting poor metastatic outcomes in treatment resistant subgroup - the "ATRESS" phenomenon.

Breast 2020 Apr 14;50:39-48. Epub 2020 Jan 14.

School of Cancer & Pharmaceutical Sciences, King's College London, Great Maze Pond, London, SE1 9RT, United Kingdom; Guy's and St Thomas NHS Foundation Trust, Great Maze Pond, London, SE1 9RT, United Kingdom. Electronic address:

Background: Major advances in breast cancer treatment have led to a reducuction in mortality. However, there are still women who are not cured. We hypothesize there is a sub-group of women with treatment-resistant cancers causing early death.

Methods: Between 1975 and 2006, 5392 women with invasive breast cancer underwent surgery at Guy's Hospital, London. Data on patient demographics, tumour characteristics, treatment regimens, local recurrence, secondary metastasis, and death were prospectively recorded. We considered four time periods (1975-1982, 1983-1990, 1991-1998, 1999-2006). Risks and time to event analysis were performed with Cox proportional hazards model and Kaplan-Meier estimation.

Results: Unadjusted hazard ratios for developing metastasis and overall mortality relative to the 1975-1982 cohort decreased steadily to 0.23 and 0.63, respectively in 1999-2006. However, metastasis-free interval shortened, with the proportion of women developing metastasis ≤5 years increasing from 73.9% to 83.0%. Furthermore, median post-metastatic survival decreased from 1.49 years to 0.94 years. Applying our risk criteria identified the presence of ±200 patients in each cohort who developed metastasis early and died within a much shorter time frame.

Conclusions: Advances in treatment have decreased the risk of metastasis and improved survival in women with invasive breast cancer over the last 40 years. Despite this, a subpopulation with shorter metastasis-free and post-metastatic survival who are unresponsive to available treatment remains. This may be due to the ATRESS phenomenon (adjuvant therapy-related shortening of survival) secondary to preselection inherent in adjuvant therapy, successful treatment of less malignant tumour cells and treatment-induced resistance in the remaining tumour clones.
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http://dx.doi.org/10.1016/j.breast.2020.01.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7375620PMC
April 2020

Real-time ex vivo perfusion of human lymph nodes invaded by cancer (REPLICANT): a feasibility study.

J Pathol 2020 03 22;250(3):262-274. Epub 2019 Dec 22.

Toby Robins Breast Cancer Now Research Centre, Breast Cancer Research Division, The Institute of Cancer Research, London, UK.

Understanding how breast cancer (BC) grows in axillary lymph nodes (ALNs), and refining how therapies might halt that process, is clinically important. However, modelling the complex ALN microenvironment is difficult, and no human models exist at present. We harvested ALNs from ten BC patients, and perfused them at 37 °C ex vivo for up to 24 h. Controlled autologous testing showed that ALNs remain viable after 24 h of ex vivo perfusion: haematoxylin and eosin-stained histological appearance and proliferation (by Ki67 immunohistochemistry) did not change significantly over time for any perfused ALN compared with a control from time-point zero. Furthermore, targeted gene expression analysis (NanoString PanCancer IO360 panel) showed that only 21/750 genes were differentially expressed between control and perfused ALNs (|log FC| > 1 and q < 0.1): none were involved in apoptosis and metabolism, but rather all 21 genes were involved in immune function and angiogenesis. During perfusion, tissue acid-base balance remained stable. Interestingly, the flow rate increased (p < 0.001) in cancer-replaced (i.e. metastasis occupied more than 90% of the surface area on multiple levels) compared to cancer-free nodes (i.e. nodes with no metastasis on multiple sections). CXCL11 transcripts were significantly more abundant in cancer-replaced nodes, while CXCL12 transcripts were significantly more abundant in cancer-free nodes. These cytokines were also detected in the circulating perfusate. Monoclonal antibodies (nivolumab and trastuzumab) were administered into a further three ALNs to confirm perfusion efficacy. These drugs saturated the nodes; nivolumab even induced cancer cell death. Normothermic ALN perfusion is not only feasible but sustains the tumour microenvironment ex vivo for scientific investigation. This model could facilitate the identification of actionable immuno-oncology targets. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
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http://dx.doi.org/10.1002/path.5367DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7065097PMC
March 2020

Graham Roberts Study protocol: first 'trials within cohort study' for bladder cancer.

BMJ Open 2019 09 26;9(9):e029468. Epub 2019 Sep 26.

Translational Oncology and Urology Research, King's College London, London, UK.

Introduction: Given the need for more bladder cancer research and the recently observed advantages of introducing the trials within cohort (TwiCs) design, the set-up of the Graham Roberts Study (Roberts Study) will provide valuable infrastructure to answer a wide variety of research questions of a clinical, mechanistic, as well as supportive care nature in the area of bladder cancer.

Methods: Using the TwiCs design, we will recruit patients aged 18 or older who are willing and able to provide signed informed consent and have a diagnosis of new or recurrent bladder cancer into this prospective cohort study. All patients must have a basic understanding of the English language. The following questionnaires will be collected at baseline and every 12 months subsequently: Functional Assessment of Chronic Illness Therapy for Bladder Cancer, the Functional Assessment of Chronic Illness Therapy-Fatigue, the Patient Heath Questionnaire-9, the standardised instrument for a generic health status (EQ-5D-5L), a Short Questionnaire to Assess Health-Enhancing Physical Activity and the Hertfordshire Short Questionnaire to Assess Diet Quality.

Ethics And Dissemination: Due to the nature of this study, we obtained full ethical clearance from the London-Fulham Research Ethics Committee (17/LO1975). All participants must provide full informed consent before recruitment onto the study. The results of this study will be published in peer-reviewed journals and data collected as part of the study will be made available to potential collaborators on an application basis.
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http://dx.doi.org/10.1136/bmjopen-2019-029468DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6773355PMC
September 2019

Frequency of Pathogenic Germline Variants in , and in Sporadic Lobular Breast Cancer.

Cancer Epidemiol Biomarkers Prev 2019 07;28(7):1162-1168

School of Cancer and Pharmaceutical Sciences, Guy's Hospital, King's College London, London, United Kingdom.

Background: Invasive lobular breast cancer (ILC) accounts for approximately 15% of invasive breast carcinomas and is commonly associated with lobular carcinoma (LCIS). Both have been shown to have higher familial risks than the more common ductal cancers. However, there are little data on the prevalence of the known high and moderate penetrance breast cancer predisposition genes in ILC. The aim of this study was to assess the frequency of germline variants in , and in sporadic ILC and LCIS diagnosed in women ages ≤60 years.

Methods: Access Array technology (Fluidigm) was used to amplify all exons of , and using a custom-made targeted sequencing panel in 1,434 cases of ILC and 368 cases of pure LCIS together with 1,611 controls.

Results: Case-control analysis revealed an excess of pathogenic variants in , and in women with ILC. was the only gene that showed an association with pure LCIS [OR = 9.90; 95% confidence interval (CI), 3.42-28.66, = 1.4 × 10] with a larger effect size seen in LCIS compared with ILC (OR = 4.31; 95% CI, 1.61-11.58, = 1.7 × 10).

Conclusions: Eleven percent of patients with ILC ages ≤40 years carried germline variants in known breast cancer susceptibility genes.

Impact: Women with ILC ages ≤40 years should be offered genetic screening using a panel of genes that includes , and .
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http://dx.doi.org/10.1158/1055-9965.EPI-18-1102DOI Listing
July 2019

Frequency of pathogenic germline variants in BRCA1, BRCA2, PALB2, CHEK2 and TP53 in ductal carcinoma in situ diagnosed in women under the age of 50 years.

Breast Cancer Res 2019 05 6;21(1):58. Epub 2019 May 6.

School of Cancer and Pharmaceutical Sciences, Guy's Hospital, King's College London, London, SE1 9RT, UK.

Introduction: Ductal carcinoma in situ (DCIS) is a non-obligate precursor of invasive ductal breast cancer, and approximately 20% of screen-detected tumours are pure DCIS. Most risk factors for breast cancer have similar associations with DCIS and IDC; however, there is limited data on the prevalence of the known high and moderate penetrance breast cancer predisposition genes in DCIS and which women with DCIS should be referred for genetic screening. The aim of this study was to assess the frequency of germline variants in BRCA2, BRCA1, CHEK2, PALB2 and TP53 in DCIS in women aged less than 50 years of age.

Methods: After DNA extraction from the peripheral blood, Access Array technology (Fluidigm) was used to amplify all exons of these five known breast cancer predisposition genes using a custom made targeted sequencing panel in 655 cases of pure DCIS presenting in women under the age of 50 years together with 1611 controls.

Results: Case-control analysis revealed an excess of pathogenic variants in BRCA2 (OR = 27.96, 95%CI 6.56-119.26, P = 2.0 × 10) and CHEK2 (OR = 8.04, 95%CI 2.93-22.05, P = 9.0 × 10), with weaker associations with PALB2 (P = 0.003), BRCA1 (P = 0.007) and TP53 (P = 0.02). For oestrogen receptor (ER)-positive DCIS the frequency of pathogenic variants was 9% under the age of 50 (14% with a family history of breast cancer) and 29% under the age of 40 (42% with a family history of breast cancer). For ER-negative DCIS, the frequency was 9% (16% with a family history of breast cancer) and 8% (11% with a family history of breast cancer) under the ages of 50 and 40, respectively.

Conclusions: This study has shown that breast tumourigenesis in women with pathogenic variants in BRCA2, CHEK2, PALB2, BRCA1 and TP53 can involve a DCIS precursor stage and that the focus of genetic testing in DCIS should be on women under the age of 40 with ER-positive DCIS.
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http://dx.doi.org/10.1186/s13058-019-1143-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6501320PMC
May 2019

Dynamics of breast-cancer relapse reveal late-recurring ER-positive genomic subgroups.

Nature 2019 03 13;567(7748):399-404. Epub 2019 Mar 13.

Department of Medicine, Division of Oncology, Stanford University School of Medicine, Stanford, CA, USA.

The rates and routes of lethal systemic spread in breast cancer are poorly understood owing to a lack of molecularly characterized patient cohorts with long-term, detailed follow-up data. Long-term follow-up is especially important for those with oestrogen-receptor (ER)-positive breast cancers, which can recur up to two decades after initial diagnosis. It is therefore essential to identify patients who have a high risk of late relapse. Here we present a statistical framework that models distinct disease stages (locoregional recurrence, distant recurrence, breast-cancer-related death and death from other causes) and competing risks of mortality from breast cancer, while yielding individual risk-of-recurrence predictions. We apply this model to 3,240 patients with breast cancer, including 1,980 for whom molecular data are available, and delineate spatiotemporal patterns of relapse across different categories of molecular information (namely immunohistochemical subtypes; PAM50 subtypes, which are based on gene-expression patterns; and integrative or IntClust subtypes, which are based on patterns of genomic copy-number alterations and gene expression). We identify four late-recurring integrative subtypes, comprising about one quarter (26%) of tumours that are both positive for ER and negative for human epidermal growth factor receptor 2, each with characteristic tumour-driving alterations in genomic copy number and a high risk of recurrence (mean 47-62%) up to 20 years after diagnosis. We also define a subgroup of triple-negative breast cancers in which cancer rarely recurs after five years, and a separate subgroup in which patients remain at risk. Use of the integrative subtypes improves the prediction of late, distant relapse beyond what is possible with clinical covariates (nodal status, tumour size, tumour grade and immunohistochemical subtype). These findings highlight opportunities for improved patient stratification and biomarker-driven clinical trials.
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http://dx.doi.org/10.1038/s41586-019-1007-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6647838PMC
March 2019

The presence of Y674/Y675 phosphorylated NTRK1 via TP53 repression of PTPN6 expression as a potential prognostic marker in neuroblastoma.

Hum Pathol 2019 04 27;86:182-192. Epub 2018 Dec 27.

Developmental Biology and Cancer Program, UCL, Great Ormond Street Institute of Child Health, London WC1N 1EH, UK. Electronic address:

The tumor suppressor TP53 promotes nerve growth factor receptor (NTRK1) -Y674/Y675 phosphorylation (NTRK1-pY674/pY675) via repression of the NTRK1 phosphatase PTPN6 in a ligand-independent manner, resulting in suppression of breast cancer cell proliferation. Moreover, NTRK1-pY674/pY675 together with low levels of PTPN6 and TP53 expression is associated with favorable disease-free survival of breast cancer patients. We determined whether in neuroblastoma this protein expression pattern impacts relapse-free survival (RFS). NTRK1-pY674/pY675, PTPN6, and TP53 expression was assessed in 98 neuroblastoma samples by immunohistochemistry. Association between expression levels and RFS was investigated by multivariate and Kaplan-Meier analysis. Mutant or wild-type TP53 was identified by sequencing tumor DNA. Tumors expressing NTRK1-pY674/pY675 and low or undetectable levels of PTPN6 and TP53 were significantly associated with 5-year RFS (P = .014) when the dataset was stratified by MYCN amplification, segmental chromosomal abnormalities and histology. Similar results were observed with tumors expressing wild-type TP53, NTRK1-pY674/pY675 and low or undetectable levels of PTPN6. Kaplan-Meier analysis demonstrated a significant correlation (P = .004), with a 50% probability of RFS (median survival 4.73 years) when present compared with 19.51% (median survival 11.63 months) when absent. Similar results were seen with non-amplified MYCN or unfavorable/undifferentiating samples and tumors from patients aged 18 months or less. Importantly, NTRK1-pY674/pY675 is an independent predictor of improved RFS. These results strongly suggest that NTRK1-pY674/pY675 together with wild-type TP53 and undetectable or low levels of PTPN6 expression is a potential biomarker of improved RFS of neuroblastoma patients. The predictive value of NTRK1-pY674/pY675 together with wild-type TP53 and low PTPN6 expression could contribute to neuroblastoma patient prognosis.
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http://dx.doi.org/10.1016/j.humpath.2018.12.003DOI Listing
April 2019

Anti-Folate Receptor Alpha-Directed Antibody Therapies Restrict the Growth of Triple-negative Breast Cancer.

Clin Cancer Res 2018 10 1;24(20):5098-5111. Epub 2018 Aug 1.

Breast Cancer Now Research Unit, School of Cancer & Pharmaceutical Sciences, King's College London, Guy's Cancer Centre, London, United Kingdom.

Highly aggressive triple-negative breast cancers (TNBCs) lack validated therapeutic targets and have high risk of metastatic disease. Folate receptor alpha (FRα) is a central mediator of cell growth regulation that could serve as an important target for cancer therapy. We evaluated FRα expression in breast cancers by genomic ( = 3,414) and IHC ( = 323) analyses and its association with clinical parameters and outcomes. We measured the functional contributions of FRα in TNBC biology by RNA interference and the antitumor functions of an antibody recognizing FRα (MOv18-IgG1), , and in human TNBC xenograft models. FRα is overexpressed in significant proportions of aggressive basal like/TNBC tumors, and in postneoadjuvant chemotherapy-residual disease associated with a high risk of relapse. Expression is associated with worse overall survival. TNBCs show dysregulated expression of thymidylate synthase, folate hydrolase 1, and methylenetetrahydrofolate reductase, involved in folate metabolism. RNA interference to deplete FRα decreased Src and ERK signaling and resulted in reduction of cell growth. An anti-FRα antibody (MOv18-IgG1) conjugated with a Src inhibitor significantly restricted TNBC xenograft growth. Moreover, MOv18-IgG1 triggered immune-dependent cancer cell death by human volunteer and breast cancer patient immune cells, and significantly restricted orthotopic and patient-derived xenograft growth. FRα is overexpressed in high-grade TNBC and postchemotherapy residual tumors. It participates in cancer cell signaling and presents a promising target for therapeutic strategies such as ADCs, or passive immunotherapy priming Fc-mediated antitumor immune cell responses. .
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http://dx.doi.org/10.1158/1078-0432.CCR-18-0652DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6193548PMC
October 2018

Macrophages are exploited from an innate wound healing response to facilitate cancer metastasis.

Nat Commun 2018 07 27;9(1):2951. Epub 2018 Jul 27.

School of Cancer and Pharmaceutical Sciences, King's College London, Faculty of Life Sciences and Medicine, Guy's Campus, London, SE1 1UL, UK.

Tumour-associated macrophages (TAMs) play an important role in tumour progression, which is facilitated by their ability to respond to environmental cues. Here we report, using murine models of breast cancer, that TAMs expressing fibroblast activation protein alpha (FAP) and haem oxygenase-1 (HO-1), which are also found in human breast cancer, represent a macrophage phenotype similar to that observed during the wound healing response. Importantly, the expression of a wound-like cytokine response within the tumour is clinically associated with poor prognosis in a variety of cancers. We show that co-expression of FAP and HO-1 in macrophages results from an innate early regenerative response driven by IL-6, which both directly regulates HO-1 expression and licenses FAP expression in a skin-like collagen-rich environment. We show that tumours can exploit this response to facilitate transendothelial migration and metastatic spread of the disease, which can be pharmacologically targeted using a clinically relevant HO-1 inhibitor.
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http://dx.doi.org/10.1038/s41467-018-05346-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6063977PMC
July 2018

ALIX Regulates Tumor-Mediated Immunosuppression by Controlling EGFR Activity and PD-L1 Presentation.

Cell Rep 2018 07;24(3):630-641

Richard Dimbleby Department of Cancer Research, Randall Division and Division of Cancer and Pharmaceutical Sciences, King's College London, Guy's Medical School Campus, London SE1 1UL, UK; KCL Breast Cancer Now Research Unit, Department of Research Oncology, Guy's Hospital, King's College London, London SE1 9RT, UK; UCL Cancer Institute, Paul O'Gorman Building, University College London, London WC1E 6DD, UK. Electronic address:

The immunosuppressive transmembrane protein PD-L1 was shown to traffic via the multivesicular body (MVB) and to be released on exosomes. A high-content siRNA screen identified the endosomal sorting complexes required for transport (ESCRT)-associated protein ALIX as a regulator of both EGFR activity and PD-L1 surface presentation in basal-like breast cancer (BLBC) cells. ALIX depletion results in prolonged and enhanced stimulation-induced EGFR activity as well as defective PD-L1 trafficking through the MVB, reduced exosomal secretion, and its redistribution to the cell surface. Increased surface PD-L1 expression confers an EGFR-dependent immunosuppressive phenotype on ALIX-depleted cells. An inverse association between ALIX and PD-L1 expression was observed in human breast cancer tissues, while an immunocompetent mouse model of breast cancer revealed that ALIX-deficient tumors are larger and show an increased immunosuppressive environment. Our data suggest that ALIX modulates immunosuppression through regulation of PD-L1 and EGFR and may, therefore, present a diagnostic and therapeutic target for BLBC.
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http://dx.doi.org/10.1016/j.celrep.2018.06.066DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6077252PMC
July 2018

Carboplatin in BRCA1/2-mutated and triple-negative breast cancer BRCAness subgroups: the TNT Trial.

Nat Med 2018 05 30;24(5):628-637. Epub 2018 Apr 30.

The Christie NHS Foundation Trust, Manchester, UK.

Germline mutations in BRCA1/2 predispose individuals to breast cancer (termed germline-mutated BRCA1/2 breast cancer, gBRCA-BC) by impairing homologous recombination (HR) and causing genomic instability. HR also repairs DNA lesions caused by platinum agents and PARP inhibitors. Triple-negative breast cancers (TNBCs) harbor subpopulations with BRCA1/2 mutations, hypothesized to be especially platinum-sensitive. Cancers in putative 'BRCAness' subgroups-tumors with BRCA1 methylation; low levels of BRCA1 mRNA (BRCA1 mRNA-low); or mutational signatures for HR deficiency and those with basal phenotypes-may also be sensitive to platinum. We assessed the efficacy of carboplatin and another mechanistically distinct therapy, docetaxel, in a phase 3 trial in subjects with unselected advanced TNBC. A prespecified protocol enabled biomarker-treatment interaction analyses in gBRCA-BC and BRCAness subgroups. The primary endpoint was objective response rate (ORR). In the unselected population (376 subjects; 188 carboplatin, 188 docetaxel), carboplatin was not more active than docetaxel (ORR, 31.4% versus 34.0%, respectively; P = 0.66). In contrast, in subjects with gBRCA-BC, carboplatin had double the ORR of docetaxel (68% versus 33%, respectively; biomarker, treatment interaction P = 0.01). Such benefit was not observed for subjects with BRCA1 methylation, BRCA1 mRNA-low tumors or a high score in a Myriad HRD assay. Significant interaction between treatment and the basal-like subtype was driven by high docetaxel response in the nonbasal subgroup. We conclude that patients with advanced TNBC benefit from characterization of BRCA1/2 mutations, but not BRCA1 methylation or Myriad HRD analyses, to inform choices on platinum-based chemotherapy. Additionally, gene expression analysis of basal-like cancers may also influence treatment selection.
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http://dx.doi.org/10.1038/s41591-018-0009-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6372067PMC
May 2018

Histological scoring of immune and stromal features in breast and axillary lymph nodes is prognostic for distant metastasis in lymph node-positive breast cancers.

J Pathol Clin Res 2018 Jan 8;4(1):39-54. Epub 2018 Jan 8.

School of Cancer and Pharmaceutical SciencesCRUK King's Health Partners Centre, King's College London, Innovation Hub, Cancer Centre at Guy's Hospital, Great Maze PondLondonUK.

The prognostic importance of lymph node (LN) status and tumour-infiltrating lymphocytes (TILs), is well established, particularly TILs in triple negative breast cancers (TNBCs). So far, few studies have interrogated changes in involved and uninvolved LNs and evaluated if their morphological patterns add valuable information for the prediction of disease progression in breast cancer. In a cohort of 309 patients enriched for TNBCs (170/309), we histologically characterised immune and stromal features in primary tumours and associated involved and uninvolved axillary LNs on routine haematoxylin and eosin stained sections. Of the 309 patients, 143 had LN-positive disease. Twenty-five histopathological features were assessed, including the degree of TIL presence, quantitative and qualitative assessment of germinal centres (GCs) and sinus histiocytosis. Multivariate and cross-validated proportional hazard regression analyses were used to identify optimal covariate sets for prediction of distant metastasis-free survival (DMFS). The degree of intratumoural and peritumoural immune infiltrate was associated with architectural changes in both uninvolved and involved LNs. By including clinicopathological characteristics as well as tumour and LN histopathological features in L2-regularised proportional hazard models, the prediction of 5-year DMFS was improved by 3-15% over the baseline in all cancers and in TNBCs. In LN-positive cancers, the combination of Salgado's classification, lymphocytic lobulitis, size and number of GCs in the uninvolved LNs and location of GCs in the involved LNs carried significant prognostic information. From these features, a multivariate cross-validation-stable risk signature was constructed, which identified low-risk groups within both LN-positive breast cancers and the LN-positive TNBCs group with a 10-year DMFS probability of 78 and 87%, respectively. This study illustrates that, by incorporating histopathological patterns of involved and uninvolved LNs combined with primary tumour immune and stromal features, the prediction of developing distant metastasis in LN-positive breast cancers can be estimated more accurately.
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http://dx.doi.org/10.1002/cjp2.87DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5783956PMC
January 2018

Repurposing Tin Mesoporphyrin as an Immune Checkpoint Inhibitor Shows Therapeutic Efficacy in Preclinical Models of Cancer.

Clin Cancer Res 2018 04 16;24(7):1617-1628. Epub 2018 Jan 16.

School of Cancer and Pharmaceutical Sciences, King's College London, Faculty of Life Sciences and Medicine, Guy's Hospital, London, United Kingdom.

Unprecedented clinical outcomes have been achieved in a variety of cancers by targeting immune checkpoint molecules. This preclinical study investigates heme oxygenase-1 (HO-1), an immunosuppressive enzyme that is expressed in a wide variety of cancers, as a potential immune checkpoint target in the context of a chemotherapy-elicited antitumor immune response. We evaluate repurposing tin mesoporphyrin (SnMP), which has demonstrated safety and efficacy targeting hepatic HO in the clinic for the treatment of hyperbilirubinemia, as an immune checkpoint blockade therapy for the treatment of cancer. SnMP and genetic inactivation of myeloid HO-1 were evaluated alongside 5-fluorouracil in an aggressive spontaneous murine model of breast cancer (). Single-cell RNA sequencing analysis, tumor microarray, and clinical survival data from breast cancer patients were used to support the clinical relevance of our observations. We demonstrate that SnMP inhibits immune suppression of chemotherapy-elicited CD8 T cells by targeting myeloid HO-1 activity in the tumor microenvironment. Microarray and survival data from breast cancer patients reveal that HO-1 is a poor prognostic factor in patients receiving chemotherapy. Single-cell RNA-sequencing analysis suggests that the myeloid lineage is a significant source of HO-1 expression, and is co-expressed with the immune checkpoints PD-L1/2 in human breast tumors. we therapeutically compare the efficacy of targeting these two pathways alongside immune-stimulating chemotherapy, and demonstrate that the efficacy of SnMP compares favorably with PD-1 blockade in preclinical models. SnMP could represent a novel immune checkpoint therapy, which may improve the immunological response to chemotherapy. .
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http://dx.doi.org/10.1158/1078-0432.CCR-17-2587DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5889101PMC
April 2018

MED12, TERT promoter and RBM15 mutations in primary and recurrent phyllodes tumours.

Br J Cancer 2018 01 9;118(2):277-284. Epub 2018 Jan 9.

School of Cancer and Pharmaceutical Sciences, Guy's Hospital, King's College London, London SE1 9RT, UK.

Background: MED12 and TERT promoter mutations have been shown to be the most common somatic mutations in phyllodes tumours (PTs). The aims of this study were to determine the frequency of these mutations in recurrent PTs, assess whether TERT promoter mutations could be helpful in distinguishing fibroadenomas (FAs) from PTs and identify novel mutations that may be driving malignant progression.

Methods: MED12 and the TERT promoter were Sanger sequenced in 75 primary PTs, 21 recurrences, 19 single FAs and 2 cases of multiple FAs with benign PTs. Whole-exome sequencing was performed on one borderline PT.

Results: Recurrent PTs and multiple FAs showed temporal discordance in MED12 but not TERT. Recurrent samples did acquire TERT mutations, with recurrent benign PTs more likely to have mutations in both genes. TERT mutations were not helpful in differentiating between benign PTs and FAs in cases of multiple FAs/PTs. Exome sequencing revealed a nonsense mutation in RBM15 and Sanger sequencing revealed another three RBM15 mutations in malignant/borderline PTs.

Conclusions: This study has shown that MED12 mutations can be heterogeneous in both synchronous and recurrent PTs unlike TERT mutations. We have also shown that RBM15 mutations may be important in the pathogenesis of borderline/malignant PTs.
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http://dx.doi.org/10.1038/bjc.2017.450DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5785756PMC
January 2018

Gene expression modules in primary breast cancers as risk factors for organotropic patterns of first metastatic spread: a case control study.

Breast Cancer Res 2017 Oct 13;19(1):113. Epub 2017 Oct 13.

School of Cancer Studies, CRUK King's Health Partners Centre, King's College London, Guy's Campus, London, SE1 1UL, UK.

Background: Metastases from primary breast cancers can involve single or multiple organs at metastatic disease diagnosis. Molecular risk factors for particular patterns of metastastic spread in a clinical population are limited.

Methods: A case-control design including 1357 primary breast cancers was used to study three distinct clinical patterns of metastasis, which occur within the first six months of metastatic disease: bone and visceral metasynchronous spread, bone-only, and visceral-only metastasis. Whole-genome expression profiles were obtained using whole genome (WG)-DASL assays from formalin-fixed paraffin-embedded (FFPE) samples. A systematic protocol was developed for handling FFPE samples together with stringent data quality controls to identify robust expression profiling data. A panel of published and novel gene sets were tested for association with these specific patterns of metastatic spread and odds ratios (ORs) were calculated.

Results: Metasynchronous metastasis to bone and viscera was found in all intrinsic breast cancer subtypes, while immunohistochemically (IHC)-defined receptor status and specific IntClust subgroups were risk factors for visceral-only or bone-only first metastases. Among gene modules, those related to proliferation increased the risk of metasynchronous metastasis (OR (95% CI) = 2.3 (1.1-4.8)) and visceral-only first metastasis (OR (95% CI) = 2.5 (1.2-5.1)) but not bone-only metastasis (OR (95% CI) = 0.97 (0.56-1.7)). A 21-gene module (BV) was identified in estrogen-receptor-positive breast cancers with metasynchronous metastasis to bone and viscera (area under the curve = 0.77), and its expression increased the risk of bone and visceral metasynchronous spread in this population. BV was further orthogonally validated with NanoString nCounter in primary breast cancers, and was reproducible in their matched lymph nodes metastases and an external cohort.

Conclusion: This case-control study of WG-DASL global expression profiles from FFPE tumour samples, after careful quality control and RNA selection, revealed that gene modules in the primary tumour have differing risks for clinical patterns of metasynchronous first metastases. Moreover, a novel gene module was identified as a putative risk factor for metasynchronous bone and visceral first metastatic spread, with potential implications for disease monitoring and treatment planning.
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http://dx.doi.org/10.1186/s13058-017-0881-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5640935PMC
October 2017

Metformin and longevity (METAL): a window of opportunity study investigating the biological effects of metformin in localised prostate cancer.

BMC Cancer 2017 Jul 21;17(1):494. Epub 2017 Jul 21.

Division of Cancer Studies, Cancer Epidemiology Group, Research Oncology, King's College London, 3rd Floor, Bermondsey Wing, Guy's Hospital, London, SE1 9RT, UK.

Background: Metformin is a biguanide oral hypoglycaemic agent commonly used for the treatment of type 2 diabetes mellitus. In addition to its anti-diabetic effect, metformin has also been associated with a reduced risk of cancer incidence of a number of solid tumours, including prostate cancer (PCa). However, the underlying biological mechanisms for these observations have not been fully characterised in PCa. One hypothesis is that the indirect insulin lowering effect may have an anti-neoplastic action as elevated insulin and insulin like growth factor - 1 (IGF-1) levels play a role in PCa development and progression. In addition, metformin is a potent activator of activated protein kinase (AMPK) which in turn inhibits the mammalian target of rapamycin (mTOR) and other signal transduction mechanisms. These direct effects can lead to reduced cell proliferation. Given its wide availability and tolerable side effect profile, metformin represents an attractive potential therapeutic option for men with PCa. Hence, the need for a clinical trial investigating its biological mechanisms in PCa.

Methods: METAL is a randomised, placebo-controlled, double-blind, window of opportunity study investigating the biological mechanism of metformin in PCa. 100 patients with newly-diagnosed, localised PCa scheduled for radical prostatectomy will be randomised 1:1 to receive metformin (1 g b.d.) or placebo for four weeks (+/- 1 week) prior to prostatectomy. Tissue will be collected from both diagnostic biopsy and prostatectomy specimens. The primary endpoint is the difference in expression levels of markers of the Fatty acid synthase (FASN)/AMPK pathway pre and post treatment between the placebo and metformin arms. Secondary endpoints include the difference in expression levels of indicators of proliferation (ki67 and TUNEL) pre and post treatment between the placebo and metformin arms. METAL is currently open to recruitment at Guy's and St Thomas' Hospital and the Royal Marsden Hospital, London.

Discussion: This randomised placebo-controlled double blinded trial of metformin vs. placebo in men with localised PCa due to undergo radical prostatectomy, aims to elucidate the mechanism of action of metformin in PCa cells, which should then enable further larger stratification trials to take place.

Trial Registration: EudraCT number 2014-005193-11 . Registered on September 09, 2015.
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http://dx.doi.org/10.1186/s12885-017-3458-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5520293PMC
July 2017

PIK3CA mutations are common in lobular carcinoma in situ, but are not a biomarker of progression.

Breast Cancer Res 2017 01 17;19(1). Epub 2017 Jan 17.

Division of Cancer Studies, Guy's Hospital, King's College London, London, SE1 9RT, UK.

Background: Lobular carcinoma in situ (LCIS) is a non-invasive breast lesion that is typically found incidentally on biopsy and is often associated with invasive lobular carcinoma (ILC). LCIS is considered by some to be a risk factor for future breast cancer rather than a true precursor lesion. The aim of this study was to identify genetic changes that could be used as biomarkers of progression of LCIS to invasive disease using cases of pure LCIS and comparing their genetic profiles to LCIS which presented contemporaneously with associated ILC, on the hypothesis that the latter represents LCIS that has already progressed.

Methods: Somatic copy number aberrations (SCNAs) were assessed by SNP array in three subgroups: pure LCIS, LCIS associated with ILC and the paired ILC. In addition exome sequencing was performed on seven fresh frozen samples of LCIS associated with ILC, to identify recurrent somatic mutations.

Results: The copy number profiles of pure LCIS and LCIS associated with ILC were almost identical. However, four SCNAs were more frequent in ILC than LCIS associated with ILC, including gain/amplification of CCND1. CCND1 protein over-expression assessed by immunohistochemical analysis in a second set of samples from 32 patients with pure LCIS and long-term follow up, was associated with invasive recurrence (P = 0.02, Fisher's exact test). Exome sequencing revealed that PIK3CA mutations were as frequent as CDH1 mutations in LCIS, but were not a useful biomarker of LCIS progression as they were as frequent in pure LCIS as in LCIS associated with ILC. We also observed heterogeneity of PIK3CA mutations and evidence of sub-clonal populations in LCIS irrespective of whether they were associated with ILC.

Conclusions: Our data shows that pure LCIS and LCIS co-existing with ILC have very similar SCNA profiles, supporting the hypothesis that LCIS is a true precursor lesion. We have provided evidence that over-expression of CCND1 may identify a subgroup of patients with pure LCIS who are more likely to develop invasive disease, in contrast to PIK3CA mutations, which occur too early in lobular tumorigenesis to be informative.
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http://dx.doi.org/10.1186/s13058-016-0789-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5240238PMC
January 2017

RORγt Innate Lymphoid Cells Promote Lymph Node Metastasis of Breast Cancers.

Cancer Res 2017 03 12;77(5):1083-1096. Epub 2017 Jan 12.

UCL Cancer Institute, Paul O'Gorman Building, University College London, London, United Kingdom.

Cancer cells tend to metastasize first to tumor-draining lymph nodes, but the mechanisms mediating cancer cell invasion into the lymphatic vasculature remain little understood. Here, we show that in the human breast tumor microenvironment (TME), the presence of increased numbers of RORγt group 3 innate lymphoid cells (ILC3) correlates with an increased likelihood of lymph node metastasis. In a preclinical mouse model of breast cancer, CCL21-mediated recruitment of ILC3 to tumors stimulated the production of the CXCL13 by TME stromal cells, which in turn promoted ILC3-stromal interactions and production of the cancer cell motile factor RANKL. Depleting ILC3 or neutralizing CCL21, CXCL13, or RANKL was sufficient to decrease lymph node metastasis. Our findings establish a role for RORγtILC3 in promoting lymphatic metastasis by modulating the local chemokine milieu of cancer cells in the TME. .
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http://dx.doi.org/10.1158/0008-5472.CAN-16-0598DOI Listing
March 2017

Splicing imbalances in basal-like breast cancer underpin perturbation of cell surface and oncogenic pathways and are associated with patients' survival.

Sci Rep 2017 01 6;7:40177. Epub 2017 Jan 6.

Guy's and St Thomas' NHS Foundation Trust and King's College London NIHR Biomedical Research Centre - Translational Bioinformatics Platform, Guy's Hospital, London, UK.

Despite advancements in the use of transcriptional information to understand and classify breast cancers, the contribution of splicing to the establishment and progression of these tumours has only recently starting to emerge. Our work explores this lesser known landscape, with special focus on the basal-like breast cancer subtype where limited therapeutic opportunities and no prognostic biomarkers are currently available. Using ExonArray analysis of 176 breast cancers and 9 normal breast tissues we demonstrate that splicing levels significantly contribute to the diversity of breast cancer molecular subtypes and explain much of the differences compared with normal tissues. We identified pathways specifically affected by splicing imbalances whose perturbation would be hidden from a conventional gene-centric analysis of gene expression. We found that a large fraction of them involve cell-to-cell communication, extracellular matrix and transport, as well as oncogenic and immune-related pathways transduced by plasma membrane receptors. We identified 247 genes in which splicing imbalances are associated with clinical patients' outcome, whilst no association was detectable at the gene expression level. These include the signaling gene TGFBR1, the proto-oncogene MYB as well as many immune-related genes such as CCR7 and FCRL3, reinforcing evidence for a role of immune components in influencing breast cancer patients' prognosis.
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http://dx.doi.org/10.1038/srep40177DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5216415PMC
January 2017

HER2-HER3 dimer quantification by FLIM-FRET predicts breast cancer metastatic relapse independently of HER2 IHC status.

Oncotarget 2016 Aug;7(32):51012-51026

Richard Dimbleby Department of Cancer Research, Randall Division and Division of Cancer Studies, King's College London, Guy's Medical School Campus, London, UK.

Overexpression of HER2 is an important prognostic marker, and the only predictive biomarker of response to HER2-targeted therapies in invasive breast cancer. HER2-HER3 dimer has been shown to drive proliferation and tumor progression, and targeting of this dimer with pertuzumab alongside chemotherapy and trastuzumab, has shown significant clinical utility. The purpose of this study was to accurately quantify HER2-HER3 dimerisation in formalin fixed paraffin embedded (FFPE) breast cancer tissue as a novel prognostic biomarker.FFPE tissues were obtained from patients included in the METABRIC (Molecular Taxonomy of Breast Cancer International Consortium) study. HER2-HER3 dimerisation was quantified using an improved fluorescence lifetime imaging microscopy (FLIM) histology-based analysis. Analysis of 131 tissue microarray cores demonstrated that the extent of HER2-HER3 dimer formation as measured by Förster Resonance Energy Transfer (FRET) determined through FLIM predicts the likelihood of metastatic relapse up to 10 years after surgery (hazard ratio 3.91 (1.61-9.5), p = 0.003) independently of HER2 expression, in a multivariate model. Interestingly there was no correlation between the level of HER2 protein expressed and HER2-HER3 heterodimer formation. We used a mathematical model that takes into account the complex interactions in a network of all four HER proteins to explain this counterintuitive finding.Future utility of this technique may highlight a group of patients who do not overexpress HER2 protein but are nevertheless dependent on the HER2-HER3 heterodimer as driver of proliferation. This assay could, if validated in a group of patients treated with, for instance pertuzumab, be used as a predictive biomarker to predict for response to such targeted therapies.
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http://dx.doi.org/10.18632/oncotarget.9963DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5239455PMC
August 2016

Two E-selectin ligands, BST-2 and LGALS3BP, predict metastasis and poor survival of ER-negative breast cancer.

Int J Oncol 2016 Jul 13;49(1):265-75. Epub 2016 May 13.

University of Lille, INSERM, U908 - CPAC, Cell Plasticity and Cancer, Lille, Villeneuve d'Ascq, France.

Distant metastases account for the majority of cancer-related deaths in breast cancer. The rate and site of metastasis differ between estrogen receptor (ER)-negative and ER-positive tumours, and metastatic fate can be very diverse even within the ER-negative group. Characterisation of new pro-metastatic markers may help to identify patients with higher risk and improve their care accordingly. Selectin ligands aberrantly expressed by cancer cells promote metastasis by enabling interaction between circulating tumour cells and endothelial cells in distant organs. These ligands consist in carbohydrate molecules, such as sialyl-Lewis x antigen (sLex), borne by glycoproteins or glycolipids on the cancer cell surface. We have previously demonstrated that the molecular scaffold presenting sLex to selectins (e.g. glycolipid vs. glycoproteins) was crucial for these interactions to occur. Moreover, we reported that detection of sLex alone in breast carcinomas was only of limited prognostic value. However, since sLex was found to be carried by several glycoproteins in cancer cells, we hypothesized that the combination of the carbohydrate with its carriers could be more relevant than each marker independently. In this study, we addressed this question by analysing sLex expression together with two glycoproteins (BST-2 and LGALS3BP), shown to interact with E-selectin in a carbohydrate-dependent manner, in a cohort of 249 invasive breast cancers. We found both glycoproteins to be associated with distant metastasis risk and poorer survival. Importantly, concomitant high expression of BST-2 with sLex defined a sub-group of patients with ER-negative tumours displaying higher risks of liver and brain metastasis and a 3-fold decreased survival rate.
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http://dx.doi.org/10.3892/ijo.2016.3521DOI Listing
July 2016

HOX transcription factors are potential targets and markers in malignant mesothelioma.

BMC Cancer 2016 Feb 11;16:85. Epub 2016 Feb 11.

Faculty of Health and Medical Sciences, University of Surrey, Guildford, UK.

Background: The HOX genes are a family of homeodomain-containing transcription factors that determine cellular identity during development and which are dys-regulated in some cancers. In this study we examined the expression and oncogenic function of HOX genes in mesothelioma, a cancer arising from the pleura or peritoneum which is associated with exposure to asbestos.

Methods: We tested the sensitivity of the mesothelioma-derived lines MSTO-211H, NCI-H28, NCI-H2052, and NCI-H226 to HXR9, a peptide antagonist of HOX protein binding to its PBX co-factor. Apoptosis was measured using a FACS-based assay with Annexin, and HOX gene expression profiles were established using RT-QPCR on RNA extracted from cell lines and primary mesotheliomas. The in vivo efficacy of HXR9 was tested in a mouse MSTO-211H flank tumor xenograft model.

Results: We show that HOX genes are significantly dysregulated in malignant mesothelioma. Targeting HOX genes with HXR9 caused apoptotic cell death in all of the mesothelioma-derived cell lines, and prevented the growth of mesothelioma tumors in a mouse xenograft model. Furthermore, the sensitivity of these lines to HXR9 correlated with the relative expression of HOX genes that have either an oncogenic or tumor suppressive function in cancer. The analysis of HOX expression in primary mesothelioma tumors indicated that these cells could also be sensitive to the disruption of HOX activity by HXR9, and that the expression of HOXB4 is strongly associated with overall survival.

Conclusion: HOX genes are a potential therapeutic target in mesothelioma, and HOXB4 expression correlates with overall survival.
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http://dx.doi.org/10.1186/s12885-016-2106-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4750173PMC
February 2016

Family history of breast cancer and its association with disease severity and mortality.

Cancer Med 2016 05 22;5(5):942-9. Epub 2016 Jan 22.

Faculty of Life Sciences and Medicine, Division of Cancer Studies, Cancer Epidemiology Group, King's College London, London, United Kingdom.

A family history (FH) of breast cancer (BC) is known to increase an individual's risk of disease onset. However, its role in disease severity and mortality is less clear. We aimed to ascertain associations between FH of BC, severity and BC-specific mortality in a hospital-based cohort of 5354 women with prospective information on FH. We included women diagnosed at Guy's and St Thomas' NHS Foundation Trust between 1975 and 2012 (n = 5354). BC severity was defined and categorized as good, moderate, and poor prognosis. Data on BC-specific mortality was obtained from the National Cancer Registry and medical records. Associations between FH and disease severity or BC-specific mortality were evaluated using proportional odds models and Cox proportional hazard regression models, respectively. Available data allowed adjustment for potential confounders (e.g., treatment, socioeconomic status, and ethnicity). FH of any degree was not associated with disease severity at time of diagnosis (adjusted proportional OR: 1.00 [95% CI: 0.85 to 1.17]), which remained true also after stratification by period of diagnosis. FH of BC was not associated with BC-mortality HR: 0.99 (95% CI: 0.93 to 1.05). We did not find evidence to support an association between FH of BC and severity and BC-specific mortality. Our results indicate that clinical management should not differ between women with and without FH, when the underlying mutation is unknown.
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http://dx.doi.org/10.1002/cam4.648DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4864823PMC
May 2016

Progression of breast cancer following locoregional ipsilateral recurrence: importance of interval time.

Br J Cancer 2016 01 10;114(1):88-95. Epub 2015 Dec 10.

King's College London, Division of Cancer Studies, Cancer Epidemiology Group, Guy's Hospital, 3rd Floor, Bermondsey Wing, London SE1 9RT, UK.

Background: Studies comparing prognosis of breast cancer (BC) patients with and without locoregional recurrence (LR) present conflicting results. We aimed to improve our understanding of the impact of LR on prognosis by examining a large cohort of patients treated at Guy's and St Thomas' NHS Foundation Trust.

Methods: Risk factors associated with BC-specific death were investigated using Cox proportional hazards regression in 5199 women diagnosed between 1975 and 2007. Breast cancer-specific death following LR was assessed with Poisson regression.

Results: Overall, 552 women (11%) developed LR, with a median follow-up time of 4.28 years. Known factors associated with BC-specific death (tumour stage, grade, and nodal status) were of significance in our data. Women with a shorter disease-free interval had a worse prognosis. For instance, the HR for BC-specific death among women undergoing mastectomy with an LR 0.5-1 year after diagnosis of their primary tumour was 6.67 (95% CI: 3.71-11.99), when compared with women who did not experience LR.

Conclusions: It often remains difficult to distinguish between a genuine LR and a new primary. The HRs for risk of BC-specific death following a second lesion suggest that they may act as a marker of systemic disease, large tumour burden, or depleted host defence. The clinically highly relevant impairment in prognosis calls for further research into the underlying mechanisms. We showed that for at least 15 years of follow-up, the prognosis in women following the occurrence of an LR may benefit from careful diagnostic and therapeutic management.
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http://dx.doi.org/10.1038/bjc.2015.314DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4716532PMC
January 2016