ORCID Profile
0000-0003-0281-2507
Current Organisations
Royal Holloway University of London
,
Institute of Development Studies
,
College of Integrated Chinese Medicine
,
University of Helsinki
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Publisher: American Association for Cancer Research (AACR)
Date: 09-2023
DOI: 10.1158/1078-0432.C.6606984
Abstract: AbstractPurpose: Limited data are available about the influence of i KIT /i and i PDGFRA /i mutations on overall survival (OS) of patients with gastrointestinal stromal tumor (GIST) treated with adjuvant imatinib. Patients and Methods: The Scandinavian Sarcoma Group XVIII/AIO multicenter trial accrued 400 patients with a high risk for GIST recurrence after macroscopically complete surgery between February 4, 2004, and September 29, 2008. The patients received adjuvant imatinib 400 mg/day for either 1 year or 3 years based on random allocation. We analyzed using conventional sequencing i KIT /i and i PDGFRA /i mutations centrally from 341 (85%) patients who had localized, centrally confirmed GIST, and correlated the results with recurrence-free survival (RFS) and OS in exploratory analyses. Results: During a median follow-up time of 10 years, 164 RFS events and 76 deaths occurred. Most patients were re-treated with imatinib when GIST recurred. Patients with i KIT /i exon 11 deletion or indel mutation treated with 3 years of adjuvant imatinib survived longer than patients treated for 1 year [10-year OS 86% versus 64%, respectively HR, 0.34 95% confidence interval (CI), 0.15–0.72 i P /i = 0.007], and also had longer RFS (10-year RFS 47% versus 29% HR, 0.48 95% CI, 0.31–0.74 i P /i 0.001). Patients with i KIT /i exon 9 mutation had unfavorable OS regardless of the duration of adjuvant imatinib. Conclusions: Compared with 1 year of imatinib, 3 years of adjuvant imatinib led to 66% reduction in the estimated risk of death and a high 10-year OS rate in the subset of patients with a i KIT /i exon 11 deletion/indel mutation. /
Publisher: American Association for Cancer Research (AACR)
Date: 19-04-2023
DOI: 10.1158/1078-0432.C.6606984.V1
Abstract: AbstractPurpose: Limited data are available about the influence of i KIT /i and i PDGFRA /i mutations on overall survival (OS) of patients with gastrointestinal stromal tumor (GIST) treated with adjuvant imatinib. Patients and Methods: The Scandinavian Sarcoma Group XVIII/AIO multicenter trial accrued 400 patients with a high risk for GIST recurrence after macroscopically complete surgery between February 4, 2004, and September 29, 2008. The patients received adjuvant imatinib 400 mg/day for either 1 year or 3 years based on random allocation. We analyzed using conventional sequencing i KIT /i and i PDGFRA /i mutations centrally from 341 (85%) patients who had localized, centrally confirmed GIST, and correlated the results with recurrence-free survival (RFS) and OS in exploratory analyses. Results: During a median follow-up time of 10 years, 164 RFS events and 76 deaths occurred. Most patients were re-treated with imatinib when GIST recurred. Patients with i KIT /i exon 11 deletion or indel mutation treated with 3 years of adjuvant imatinib survived longer than patients treated for 1 year [10-year OS 86% versus 64%, respectively HR, 0.34 95% confidence interval (CI), 0.15–0.72 i P /i = 0.007], and also had longer RFS (10-year RFS 47% versus 29% HR, 0.48 95% CI, 0.31–0.74 i P /i 0.001). Patients with i KIT /i exon 9 mutation had unfavorable OS regardless of the duration of adjuvant imatinib. Conclusions: Compared with 1 year of imatinib, 3 years of adjuvant imatinib led to 66% reduction in the estimated risk of death and a high 10-year OS rate in the subset of patients with a i KIT /i exon 11 deletion/indel mutation. /
Publisher: Oxford University Press (OUP)
Date: 05-06-2013
DOI: 10.1093/JNCI/DJT121
Publisher: American Association for Cancer Research (AACR)
Date: 09-2023
Publisher: Research Square Platform LLC
Date: 03-02-2023
DOI: 10.21203/RS.3.RS-2408990/V1
Abstract: The discovery of molecular subtypes has corroborated the heterogeneity of breast cancers. But in clinical routine, treatment selection relies on measuring the aggressiveness of the tumor via histopathology, which is routinely based on grading, a prognostic yet laborious, poorly reproducible, and subjective procedure defined more than 30 years ago, before molecular subtypes existed. In this paper, we present an interpretable deep learning-based computer-aided diagnosis method to automate mitotic count , one of the components of grading the method complies with current guidelines and automates hot-spot finding on full digital whole-slide images of routinely prepared pathologic slides stained with hematoxylin and eosin. We use the computer model to query the current “one-size-fits-all” mitotic count procedure by investigating subtype-specific prognostic value of mitotic count using an external independent large-scale multicentric dataset of 1,709 breast cancers. We show that for human epidermal growth factor-2 (HER2) positive tumors, mitotic count was not prognostic. In hormone-receptor positive/HER2 negative cancers, an average mitotic count density different from clinically used cut offs predicted worse recurrence free survival in multivariable analysis, adjusted for known clinical prognosticators. We provided some first experimental evidence that the prognostic role of mitotic count should be reviewed.
Publisher: American Medical Association (AMA)
Date: 08-2020
Publisher: American Association for Cancer Research (AACR)
Date: 19-04-2023
DOI: 10.1158/1078-0432.22658850.V1
Abstract: Kaplan-Meier estimates of recurrence-free survival of patients with KIT exon 11 substitution mutation (A) and patients with KIT exon 9 mutation (B). The 5-year and 10-year survival rates are shown. Censored patients are indicated with a bar
Publisher: American Society of Clinical Oncology (ASCO)
Date: 04-2018
Abstract: Phosphatidylinositol-4, 5-bisphosphate 3-kinase catalytic subunit alpha ( PIK3CA) mutations are frequently observed in primary breast cancer. We evaluated their prognostic relevance by performing a pooled analysis of in idual patient data. Associations between PIK3CA status and clinicopathologic characteristics were tested by applying Cox regression models adjusted for age, tumor size, nodes, grade, estrogen receptor (ER) status, human epidermal growth factor receptor 2 (HER2) status, treatment, and study. Invasive disease-free survival (IDFS) was the primary end point distant disease-free survival (DDFS) and overall survival (OS) were also assessed, overall and by breast cancer subtypes. Data from 10,319 patients from 19 studies were included (median OS follow-up, 6.9 years) 1,787 patients (17%) received chemotherapy, 4,036 (39%) received endocrine monotherapy, 3,583 (35%) received both, and 913 (9%) received none or their treatment was unknown. PIK3CA mutations occurred in 32% of patients, with significant associations with ER positivity, increasing age, lower grade, and smaller size (all P .001). Prevalence of PIK3CA mutations was 18%, 22%, and 37% in the ER-negative/HER2-negative, HER2-positive, and ER-positive/HER2-negative subtypes, respectively. In univariable analysis, PIK3CA mutations were associated with better IDFS (HR, 0.77 95% CI, 0.71 to 0.84 P .001), with evidence for a stronger effect in the first years of follow-up (0 to 5 years: HR, 0.73 95% CI, 0.66 to 0.81 P .001 5 to 10 years: HR, 0.82 95% CI, 0.68 to 0.99 P = .037) 10 years: (HR, 1.15 95% CI, 0.84 to 1.58 P = .38 P heterogeneity = .02). In multivariable analysis, PIK3CA genotype remained significant for improved IDFS ( P = .043), but not for the DDFS and OS end points. In this large pooled analysis, PIK3CA mutations were significantly associated with a better IDFS, DDFS, and OS, but had a lesser prognostic effect after adjustment for other prognostic factors.
Publisher: The Ohio State University Libraries
Date: 13-09-2021
Abstract: This article explores COVID-19 related experiences of disabled people in Bangladesh, Kenya, Nigeria, Nepal and Uganda. Narrative interviews generated storied responses, focussing on respondents' priorities, which enabled us to hear what was most significant for them and their families. 143 interviews were conducted online or by phone by 7 local researchers (3 disabled), with appropriate inclusive support. Nearly everyone was interviewed twice to capture the progression of impacts over time. The data was analysed thematically through a virtual participatory approach.An overarching 'subjective' theme of feelings experienced by the participants was labelled 'destabilisation, disorientation and uncertainty'. We also identified 'concrete' or material impacts. People experienced various dilemmas such as choosing between securing food and keeping safe, and tensions between receiving support and feeling increased vulnerability or dependence, with interplay between the emotions of fear, loss and hope. We found both the concept of liminality and grief models productive in understanding the progression of participants' experiences. Disabled people reported the same feelings, difficulties and impacts as others, reported in other literature, but often their pre-existing disadvantages have been exacerbated by the pandemic, including poverty, gender and impairment related stresses and discrimination, inaccessible services or relief, and exclusion from government initiatives.
Publisher: American Association for Cancer Research (AACR)
Date: 09-2023
Publisher: American Association for Cancer Research (AACR)
Date: 19-04-2023
DOI: 10.1158/1078-0432.22658856.V1
Abstract: Study protocol
Publisher: American Association for Cancer Research (AACR)
Date: 09-2023
Publisher: American Association for Cancer Research (AACR)
Date: 19-04-2023
DOI: 10.1158/1078-0432.22658856
Abstract: Study protocol
Publisher: American Association for Cancer Research (AACR)
Date: 09-2023
Publisher: American Association for Cancer Research (AACR)
Date: 19-04-2023
DOI: 10.1158/1078-0432.22658853
Abstract: Kaplan-Meier estimates of recurrence-free survival (A, C) and overall survival (B, D) of patients with KIT exon 11 deletion mutation (A, B) and patients with KIT exon 11 indel mutation (C, D)
Publisher: American Association for Cancer Research (AACR)
Date: 09-2023
Publisher: American Association for Cancer Research (AACR)
Date: 19-04-2023
DOI: 10.1158/1078-0432.22658850
Abstract: Kaplan-Meier estimates of recurrence-free survival of patients with KIT exon 11 substitution mutation (A) and patients with KIT exon 9 mutation (B). The 5-year and 10-year survival rates are shown. Censored patients are indicated with a bar
Publisher: American Association for Cancer Research (AACR)
Date: 09-2023
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/1078-0432.CCR-22-3980
Abstract: Limited data are available about the influence of KIT and PDGFRA mutations on overall survival (OS) of patients with gastrointestinal stromal tumor (GIST) treated with adjuvant imatinib. The Scandinavian Sarcoma Group XVIII/AIO multicenter trial accrued 400 patients with a high risk for GIST recurrence after macroscopically complete surgery between February 4, 2004, and September 29, 2008. The patients received adjuvant imatinib 400 mg/day for either 1 year or 3 years based on random allocation. We analyzed using conventional sequencing KIT and PDGFRA mutations centrally from 341 (85%) patients who had localized, centrally confirmed GIST, and correlated the results with recurrence-free survival (RFS) and OS in exploratory analyses. During a median follow-up time of 10 years, 164 RFS events and 76 deaths occurred. Most patients were re-treated with imatinib when GIST recurred. Patients with KIT exon 11 deletion or indel mutation treated with 3 years of adjuvant imatinib survived longer than patients treated for 1 year [10-year OS 86% versus 64%, respectively HR, 0.34 95% confidence interval (CI), 0.15–0.72 P = 0.007], and also had longer RFS (10-year RFS 47% versus 29% HR, 0.48 95% CI, 0.31–0.74 P & 0.001). Patients with KIT exon 9 mutation had unfavorable OS regardless of the duration of adjuvant imatinib. Compared with 1 year of imatinib, 3 years of adjuvant imatinib led to 66% reduction in the estimated risk of death and a high 10-year OS rate in the subset of patients with a KIT exon 11 deletion/indel mutation.
Publisher: Springer Science and Business Media LLC
Date: 29-11-2021
DOI: 10.1038/S41467-021-27220-9
Abstract: Breast cancer is now globally the most frequent cancer and leading cause of women’s death. Two thirds of breast cancers express the luminal estrogen receptor-positive (ERα + ) phenotype that is initially responsive to antihormonal therapies, but drug resistance emerges. A major barrier to the understanding of the ERα-pathway biology and therapeutic discoveries is the restricted repertoire of luminal ERα + breast cancer models. The ERα + phenotype is not stable in cultured cells for reasons not fully understood. We examine 400 patient-derived breast epithelial and breast cancer explant cultures (PDECs) grown in various three-dimensional matrix scaffolds, finding that ERα is primarily regulated by the matrix stiffness. Matrix stiffness upregulates the ERα signaling via stress-mediated p38 activation and H3K27me3-mediated epigenetic regulation. The finding that the matrix stiffness is a central cue to the ERα phenotype reveals a mechanobiological component in breast tissue hormonal signaling and enables the development of novel therapeutic interventions. Subject terms: ER-positive (ER + ), breast cancer, ex vivo model, preclinical model, PDEC, stiffness, p38 SAPK.
Publisher: American Association for Cancer Research (AACR)
Date: 19-04-2023
DOI: 10.1158/1078-0432.22658847.V1
Abstract: Kaplan-Meier estimates of recurrence-free survival (A, C, E) and overall survival (B, D, F) of patients with KIT exon 11 insertion or duplication mutation (A, B), patients with PDGFRA exon 18 D842V mutation (C, D), and patients with no detected KIT or PDGFRA mutation (E, F). The 5-year and 10-year survival rates are shown. Censored patients are indicated with a bar.
Publisher: Springer Science and Business Media LLC
Date: 05-08-2019
Publisher: American Association for Cancer Research (AACR)
Date: 09-2023
Publisher: American Medical Association (AMA)
Date: 2019
Publisher: Springer Science and Business Media LLC
Date: 12-2021
DOI: 10.1038/S41523-021-00346-1
Abstract: The advent of immune-checkpoint inhibitors (ICI) in modern oncology has significantly improved survival in several cancer settings. A subgroup of women with breast cancer (BC) has immunogenic infiltration of lymphocytes with expression of programmed death-ligand 1 (PD-L1). These patients may potentially benefit from ICI targeting the programmed death 1 (PD-1)/PD-L1 signaling axis. The use of tumor-infiltrating lymphocytes (TILs) as predictive and prognostic biomarkers has been under intense examination. Emerging data suggest that TILs are associated with response to both cytotoxic treatments and immunotherapy, particularly for patients with triple-negative BC. In this review from The International Immuno-Oncology Biomarker Working Group , we discuss (a) the biological understanding of TILs, (b) their analytical and clinical validity and efforts toward the clinical utility in BC, and (c) the current status of PD-L1 and TIL testing across different continents, including experiences from low-to-middle-income countries, incorporating also the view of a patient advocate. This information will help set the stage for future approaches to optimize the understanding and clinical utilization of TIL analysis in patients with BC.
Publisher: Springer Science and Business Media LLC
Date: 03-08-2015
Publisher: American Association for Cancer Research (AACR)
Date: 14-01-2016
DOI: 10.1158/0008-5472.CAN-15-1567
Abstract: The HER2/ErbB2 monoclonal antibody (mAb) trastuzumab is combined with chemotherapy as a standard-of-care for newly diagnosed HER2+ breast cancer patients, but some patients treated with this combination therapy experience early relapse. Our analysis of data from a clinical trial evaluating the efficacy of chemotherapy plus/minus trastuzumab suggested that the magnitude of trastuzumab benefit on distant disease-free survival was higher for increasing expression of the IL21 receptor (IL21R). Therefore, we investigated a possible role for IL21 signaling in promoting HER2 mAb therapeutic efficacy. We found that IL21R-deficient mice and wild-type mice treated with a neutralizing anti-IL21 mAb were less susceptible to trastuzumab-like anti-ErbB2 therapy. Furthermore, IL21R expression on CD8+ T cells, but not on natural killer cells, was required for optimal anti-ErbB2 mAb efficacy, and IL21 expression was enhanced in tumor-infiltrating CD4+ T lymphocytes after anti-ErbB2 therapy. Finally, we found that administering recombinant IL21 in combination with anti-ErbB2 therapy was therapeutic against primary tumors and experimental metastases in mice. Collectively, our findings suggest that elevating IL21 signaling may enhance trastuzumab efficacy, thus constituting a novel candidate strategy to overcome trastuzumab resistance and improve patient survival. Cancer Res 76(2) 264–74. ©2016 AACR.
Publisher: Impact Journals, LLC
Date: 03-09-2015
Publisher: Elsevier BV
Date: 05-2015
DOI: 10.1016/J.EJCA.2015.02.015
Abstract: Metastatic gastrointestinal stromal tumour (GIST) is generally an incurable disease with variable response to imatinib. We aimed to develop prognostic nomograms to predict overall survival (OS) and progression-free survival (PFS) for patients treated with imatinib. Nomograms were developed in a training cohort (n=330) of patients treated in a randomised trial (EORTC-ISG-AGITG 62005 phase III study) using Cox regression models, and validated in patients (n=236) treated in routine clinical care from six referral centres. Nomogram performance was assessed by calculating the c statistic. A classification based on the nomograms' scores was generated to group patients according to risk. Nomogram risk factors for OS and PFS were size of the largest metastasis, tumour genotype, primary tumour mitotic count, haemoglobin and blood neutrophil count at commencement of imatinib. The nomograms predicted survival with a c statistic of 0.75 (training) and 0.62 (validation) for OS, and 0.69 (training) and 0.62 (validation) for PFS. When tested in the validation cohort, the nomograms discriminated well the high and intermediate risk from low risk patients (hazard ratio [HR] for OS 3.83, 95% confidence interval [CI] 1.71-8.56 and 2.48, 95% CI 1.12-5.50 for PFS 2.84, 95% CI 1.66-4.87 and 1.45, 95% CI 0.87-2.41, respectively). The nomograms predicted the risk of GIST progression and death with good discrimination of risk groups, and may be of value for patient counselling and risk stratification.
Publisher: American Association for Cancer Research (AACR)
Date: 19-04-2023
DOI: 10.1158/1078-0432.22658853.V1
Abstract: Kaplan-Meier estimates of recurrence-free survival (A, C) and overall survival (B, D) of patients with KIT exon 11 deletion mutation (A, B) and patients with KIT exon 11 indel mutation (C, D)
Publisher: American Association for Cancer Research (AACR)
Date: 09-2023
Publisher: American Association for Cancer Research (AACR)
Date: 19-04-2023
DOI: 10.1158/1078-0432.22658847
Abstract: Kaplan-Meier estimates of recurrence-free survival (A, C, E) and overall survival (B, D, F) of patients with KIT exon 11 insertion or duplication mutation (A, B), patients with PDGFRA exon 18 D842V mutation (C, D), and patients with no detected KIT or PDGFRA mutation (E, F). The 5-year and 10-year survival rates are shown. Censored patients are indicated with a bar.
Publisher: American Association for Cancer Research (AACR)
Date: 09-2023
Publisher: Elsevier BV
Date: 11-2020
Publisher: Wiley
Date: 07-2022
DOI: 10.1002/JID.3679
Publisher: Springer Science and Business Media LLC
Date: 12-05-2020
DOI: 10.1038/S41523-020-0155-1
Abstract: Stromal tumor-infiltrating lymphocytes (sTILs) are a potential predictive biomarker for immunotherapy response in metastatic triple-negative breast cancer (TNBC). To incorporate sTILs into clinical trials and diagnostics, reliable assessment is essential. In this review, we propose a new concept, namely the implementation of a risk-management framework that enables the use of sTILs as a stratification factor in clinical trials. We present the design of a biomarker risk-mitigation workflow that can be applied to any biomarker incorporation in clinical trials. We demonstrate the implementation of this concept using sTILs as an integral biomarker in a single-center phase II immunotherapy trial for metastatic TNBC (TONIC trial, NCT02499367), using this workflow to mitigate risks of suboptimal inclusion of sTILs in this specific trial. In this review, we demonstrate that a web-based scoring platform can mitigate potential risk factors when including sTILs in clinical trials, and we argue that this framework can be applied for any future biomarker-driven clinical trial setting.
Publisher: Springer Science and Business Media LLC
Date: 12-05-2020
DOI: 10.1038/S41523-020-0156-0
Abstract: Stromal tumor-infiltrating lymphocytes (sTILs) are important prognostic and predictive biomarkers in triple-negative (TNBC) and HER2-positive breast cancer. Incorporating sTILs into clinical practice necessitates reproducible assessment. Previously developed standardized scoring guidelines have been widely embraced by the clinical and research communities. We evaluated sources of variability in sTIL assessment by pathologists in three previous sTIL ring studies. We identify common challenges and evaluate impact of discrepancies on outcome estimates in early TNBC using a newly-developed prognostic tool. Discordant sTIL assessment is driven by heterogeneity in lymphocyte distribution. Additional factors include: technical slide-related issues scoring outside the tumor boundary tumors with minimal assessable stroma including lymphocytes associated with other structures and including other inflammatory cells. Small variations in sTIL assessment modestly alter risk estimation in early TNBC but have the potential to affect treatment selection if cutpoints are employed. Scoring and averaging multiple areas, as well as use of reference images, improve consistency of sTIL evaluation. Moreover, to assist in avoiding the pitfalls identified in this analysis, we developed an educational resource available at itfalls .
Publisher: Elsevier BV
Date: 10-2012
Publisher: American Association for Cancer Research (AACR)
Date: 09-2023
Publisher: American Association for Cancer Research (AACR)
Date: 19-04-2023
DOI: 10.1158/1078-0432.22658841
Abstract: Representativeness of Study Participants
Publisher: American Society of Clinical Oncology (ASCO)
Date: 03-2019
DOI: 10.1200/JCO.18.01010
Abstract: The aim of the current study was to conduct a pooled analysis of studies that have investigated the prognostic value of tumor-infiltrating lymphocytes (TILs) in early-stage triple negative breast cancer (TNBC). Participating studies had evaluated the percentage infiltration of stromally located TILs (sTILs) that were quantified in the same manner in patient diagnostic s les of early-stage TNBC treated with anthracycline-based chemotherapy with or without taxanes. Cox proportional hazards regression models stratified by trial were used for invasive disease-free survival (iDFS primary end point), distant disease-free survival (D-DFS), and overall survival (OS), fitting sTILs as a continuous variable adjusted for clinicopathologic factors. We collected in idual data from 2,148 patients from nine studies. Average age was 50 years (range, 22 to 85 years), and 33% of patients were node negative. The average value of sTILs was 23% (standard deviation, 20%), and 77% of patients had 1% or more sTILs. sTILs were significantly lower with older age ( P = .001), larger tumor size ( P = .01), more nodal involvement ( P = .02), and lower histologic grade ( P = .001). A total of 736 iDFS and 548 D-DFS events and 533 deaths were observed. In the multivariable model, sTILs added significant independent prognostic information for all end points (likelihood ratio χ 2 , 48.9 iDFS P .001 χ 2 , 55.8 D-DFS P .001 χ 2 , 48.5 OS P .001). Each 10% increment in sTILs corresponded to an iDFS hazard ratio of 0.87 (95% CI, 0.83 to 0.91) for iDFS, 0.83 (95% CI, 0.79 to 0.88) for D-DFS, and 0.84 (95% CI, 0.79 to 0.89) for OS. In node-negative patients with sTILs ≥ 30%, 3-year iDFS was 92% (95% CI, 89% to 98%), D-DFS was 97% (95% CI, 95% to 99%), and OS was 99% (95% CI, 97% to 100%). This pooled data analysis confirms the strong prognostic role of sTILs in early-stage TNBC and excellent survival of patients with high sTILs after adjuvant chemotherapy and supports the integration of sTILs in a clinicopathologic prognostic model for patients with TNBC. This model can be found at www.tilsinbreastcancer.org .
Publisher: Elsevier BV
Date: 08-2014
Abstract: We have previously shown the prognostic importance of tumor-infiltrating lymphocytes (TILs) in newly diagnosed triple-negative breast cancer (TNBC) using tumor s les from a large clinical trial cohort. In this study, we aimed to validate these findings and also investigate associations with trastuzumab benefit in HER2-overexpressing disease (HER2+). A prospective-retrospective study was conducted using s les from the FinHER adjuvant, phase III trial that enrolled 1010 early-stage BC patients, 778 of whom were HER2-non lified. Those with HER2+ disease (n = 232) were randomized to 9 weeks of trastuzumab or no trastuzumab in addition to chemotherapy. Two pathologists independently quantified stromal TILs in 935 (92.6%) available slides. The primary end point of distant disease-free survival (DDFS) and interactions with trastuzumab were studied in Cox regression models. Confirming our previous findings, in TNBC (n = 134) each 10% increase in TILs was significantly associated with decreased distant recurrence in TNBC for DDFS the hazard ratio adjusted for clinicopathological factors: 0.77 95% confidence interval (CI) 0.61-0.98, P = 0.02. In HER2+ BC (n = 209), each 10% increase in lymphocytic infiltration was significantly associated with decreased distant recurrence in patients randomized to the trastuzumab arm (DDFS P interaction = 0.025). Higher levels of TILs present at diagnosis were significantly associated with decreased distant recurrence rates in primary TNBC. These results confirm our previous data and further support that TILs should be considered as a robust prognostic factor in this BC subtype. We also report for the first time an association between higher levels of TILs and increased trastuzumab benefit in HER2+ disease. Further research into why some TN and HER2+ BCs can or cannot generate a host antitumor immune response and how trastuzumab can favorably alter the immune microenvironment is warranted.
Publisher: American Association for Cancer Research (AACR)
Date: 15-10-2017
DOI: 10.1158/0008-5472.CAN-17-0707
Abstract: Expression of the ectonucleotidase CD73 by tumor cells, stromal cells, and immune cells is associated in cancer with immune suppression. In this study, we investigated the role of CD73 on the activity of the anti-HER2/ErbB2 monoclonal antibody (mAb) trastuzumab. In a prospective, randomized phase III clinical trial evaluating the activity of trastuzumab, high levels of CD73 gene expression were associated significantly with poor clinical outcome. In contrast, high levels of PD-1 and PD-L1 were associated with improved clinical outcome. In immunocompetent mouse models of HER2/ErbB2–driven breast cancer, CD73 expression by tumor cells and host cells significantly suppressed immune-mediated responses mediated by anti-ErbB2 mAb. Furthermore, anti-CD73 mAb therapy enhanced the activity of anti-ErbB2 mAb to treat engrafted or spontaneous tumors as well as lung metastases. Gene ontology enrichment analysis from gene-expression data revealed a positive association of CD73 expression with extracellular matrix organization, TGFβ genes, epithelial-to-mesenchymal transition (EMT) transcription factors and hypoxia-inducible-factor (HIF)-1 gene signature. Human mammary cells treated with TGFβ or undergoing EMT upregulated CD73 cell-surface expression, confirming roles for these pathways. In conclusion, our findings establish CD73 in mediating resistance to trastuzumab and provide new insights into how CD73 is regulated in breast cancer. Cancer Res 77(20) 5652–63. ©2017 AACR.
Publisher: American Association for Cancer Research (AACR)
Date: 19-04-2023
DOI: 10.1158/1078-0432.22658841.V1
Abstract: Representativeness of Study Participants
Publisher: Wiley
Date: 07-2022
DOI: 10.1002/JID.3692
Abstract: Diverse approaches to promoting disability inclusive employment aim to transform workplaces into truly inclusive environments, usually with intervention strategies targeting two main groups: employers and jobseekers with disabilities. However, they do not always consider other relevant stakeholders or address the relationships and interactions between erse actors in the wider social ecosystem. These approaches often neglect deeper ‘vexing’ difficulties which block progress towards disability inclusive work environments. Most interventions rightly embrace hegemonic ‘social models of disability’ and use human rights arguments but may neglect entrenched structural factors. Disability inclusive employment is complex, with unaddressed invisible aspects that continue to limit progress. We explore some key relevant disability concepts and then interrogate evidence from the ‘Inclusion Works’ programme working in four middle‐ and low‐income countries, considering some intractable barriers underlying the slow movement towards inclusive employment. Finally, we propose that a more participatory action orientated approach involving disabled people and others is needed to both generate deeper understanding and provide pathways towards new solutions to obstinate problems through progressive action learning processes in context. Programmatic interventions that work across the levels of the ecosystem and address power relations and interactions between stakeholders could lead to more substantial forms of disability inclusive employment.
Publisher: Springer Science and Business Media LLC
Date: 11-01-2022
DOI: 10.1038/S41523-021-00362-1
Abstract: The importance of integrating biomarkers into the TNM staging has been emphasized in the 8 th Edition of the American Joint Committee on Cancer (AJCC) Staging system. In a pooled analysis of 2148 TNBC-patients in the adjuvant setting, TILs are found to strongly up and downstage traditional pathological-staging in the Pathological and Clinical Prognostic Stage Groups from the AJJC 8 th edition Cancer Staging System. This suggest that clinical and research studies on TNBC should take TILs into account in addition to stage, as for ex le patients with stage II TNBC and high TILs have a better outcome than patients with stage I and low TILs.
Publisher: American Association for Cancer Research (AACR)
Date: 09-2023
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Heikki Joensuu.