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Breast Neoplasms: HELP
Articles by Erik J. Blok
Based on 11 articles published since 2010
(Why 11 articles?)
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Between 2010 and 2020, E. J. Blok wrote the following 11 articles about Breast Neoplasms.
 
+ Citations + Abstracts
1 Review Systematic review of the clinical and economic value of gene expression profiles for invasive early breast cancer available in Europe. 2018

Blok, E J / Bastiaannet, E / van den Hout, W B / Liefers, G J / Smit, V T H B M / Kroep, J R / van de Velde, C J H. ·Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands; Department of Medical Oncology, Leiden University Medical Center, Leiden, The Netherlands. · Department of Medical Decision Making, Leiden University Medical Center, Leiden, The Netherlands. · Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands. · Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands. · Department of Medical Oncology, Leiden University Medical Center, Leiden, The Netherlands. · Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands. Electronic address: c.j.h.van_de_velde@lumc.nl. ·Cancer Treat Rev · Pubmed #29175678.

ABSTRACT: Gene expression profiles with prognostic capacities have shown good performance in multiple clinical trials. However, with multiple assays available and numerous types of validation studies performed, the added value for daily clinical practice is still unclear. In Europe, the MammaPrint, OncotypeDX, PAM50/Prosigna and Endopredict assays are commercially available. In this systematic review, we aim to assess these assays on four important criteria: Assay development and methodology, clinical validation, clinical utility and economic value. We performed a literature search covering PubMed, Embase, Web of Science and Cochrane, for studies related to one or more of the four selected assays. We identified 147 papers for inclusion in this review. MammaPrint and OncotypeDX both have evidence available, including level IA clinical trial results for both assays. Both assays provide prognostic information. Predictive value has only been shown for OncotypeDX. In the clinical utility studies, a higher reduction in chemotherapy was achieved by OncotypeDX, although the number of available studies differ considerably between tests. On average, economic evaluations estimate that genomic testing results in a moderate increase in total costs, but that these costs are acceptable in relation to the expected improved patient outcome. PAM50/prosigna and EndoPredict showed comparable prognostic capacities, but with less economical and clinical utility studies. Furthermore, for these assays no level IA trial data are available yet. In summary, all assays have shown excellent prognostic capacities. The differences in the quantity and quality of evidence are discussed. Future studies shall focus on the selection of appropriate subgroups for testing and long-term outcome of validation trials, in order to determine the place of these assays in daily clinical practice.

2 Review Extended adjuvant endocrine therapy in hormone-receptor positive early breast cancer: current and future evidence. 2015

Blok, E J / Derks, M G M / van der Hoeven, J J M / van de Velde, C J H / Kroep, J R. ·Department of Surgery, Leiden University Medical Centre, Leiden, The Netherlands; Department of Medical Oncology, Leiden University Medical Centre, Leiden, The Netherlands. Electronic address: e.j.blok@lumc.nl. · Department of Surgery, Leiden University Medical Centre, Leiden, The Netherlands. · Department of Medical Oncology, Leiden University Medical Centre, Leiden, The Netherlands. ·Cancer Treat Rev · Pubmed #25698635.

ABSTRACT: The optimal duration and regimen of adjuvant hormonal therapy for premenopausal and postmenopausal patients with hormone receptor positive early breast cancer has not yet been established. This review will give an overview of published and ongoing studies concerning extended endocrine treatment. Most of the currently published studies are based on the adjuvant treatment regime of 5 years tamoxifen, which has been proven to be inferior compared to aromatase inhibitor (AI)-containing regimes. Therefore, until today, there is no clear evidence for the extension of endocrine therapy after upfront AI-based adjuvant treatment regimes. Multiple clinical trials, which will be discussed in this review, are ongoing to elucidate on this matter. We emphasize the need for tailoring of extended adjuvant endocrine treatment. The quest for predictive biomarkers, which are currently being investigated in the context of decision-making whether or not to start adjuvant chemotherapy, should be expanded to include the feasibility of extended endocrine treatment based on these markers. By tailoring the extension of endocrine treatment, overtreatment, side effects and unnecessary costs will be prevented.

3 Clinical Trial Treatment decisions and the impact of adverse events before and during extended endocrine therapy in postmenopausal early breast cancer. 2018

Blok, Erik J / Kroep, Judith R / Meershoek-Klein Kranenbarg, Elma / Duijm-de Carpentier, Marjolijn / Putter, Hein / Liefers, Gerrit-Jan / Nortier, Johan W R / Rutgers, Emiel J Th / Seynaeve, Caroline M / van de Velde, Cornelis J H / Anonymous9770942. ·Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands; Department of Medical Oncology, Leiden University Medical Center, Leiden, The Netherlands. · Department of Medical Oncology, Leiden University Medical Center, Leiden, The Netherlands. · Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands. · Department of Medical Statistics, Leiden University Medical Center, Leiden, The Netherlands. · Department of Surgery, Netherlands Cancer Institute, Amsterdam, The Netherlands. · Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands. · Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands. Electronic address: c.j.h.van_de_velde@lumc.nl. ·Eur J Cancer · Pubmed #29635145.

ABSTRACT: BACKGROUND: Extended endocrine therapy beyond 5 years for postmenopausal breast cancer has been studied within multiple phase III trials. Treatment compliance in these trials is generally poor. In this analysis, we aimed to determine factors that were associated with participation in the phase III Investigation on the Duration of Extended Adjuvant Letrozole (IDEAL) trial and with early treatment discontinuation, and how this influenced survival outcome. METHODS: In the IDEAL trial, postmenopausal patients were randomised between 2.5 or 5 years of extended letrozole, after completing 5 years of endocrine therapy for hormone receptor-positive early breast cancer. A subgroup of this population participated earlier in the Tamoxifen Exemestane Adjuvant Multinational trial (5 years of exemestane or 2.5 years of tamoxifen followed by exemestane as primary adjuvant therapy) in which we explored which factors were determinative for enrolment in the IDEAL study. In the IDEAL cohort, we evaluated which factors predicted for early treatment discontinuation and the effect of early treatment discontinuation on disease-free survival (DFS). RESULTS: Nodal status, younger age and adjuvant chemotherapy were significantly associated with higher enrolment in the IDEAL trial. In the IDEAL cohort, adverse events (AEs), the type of primary endocrine therapy and the interval between primary and extended therapy were associated with early treatment discontinuation. Among the reported AEs, depressive feelings (56%) were most frequently associated with early treatment discontinuation. Early treatment discontinuation was not associated with worse DFS (hazard ratio [HR] = 1.02, 95% confidence interval = 0.76-1.37). CONCLUSIONS: In this analysis, we found that risk factors were most strongly associated enrolment in the IDEAL trial. In contrast, patient experiences were the most significant factors leading to early treatment discontinuation, with no effect on DFS.

4 Clinical Trial Relevant factors for the optimal duration of extended endocrine therapy in early breast cancer. 2018

Blok, Erik J / Kroep, Judith R / Meershoek-Klein Kranenbarg, Elma / Duijm-de Carpentier, Marjolijn / Putter, Hein / Liefers, Gerrit-Jan / Nortier, Johan W R / Rutgers, Emiel J Th / Seynaeve, Caroline M / van de Velde, Cornelis J H / Anonymous6710929. ·Department of Surgery, Leiden University Medical Center, 2300 RC, Leiden, The Netherlands. · Department of Medical Oncology, Leiden University Medical Center, P.O. Box 9600, Leiden, The Netherlands. · Department of Medical Statistics, Leiden University Medical Center, Leiden, The Netherlands. · Department of Surgery, Netherlands Cancer Institute, Amsterdam, The Netherlands. · Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands. · Department of Surgery, Leiden University Medical Center, 2300 RC, Leiden, The Netherlands. c.j.h.van_de_velde@lumc.nl. ·Breast Cancer Res Treat · Pubmed #29230665.

ABSTRACT: PURPOSE: For postmenopausal patients with hormone receptor-positive early breast cancer, the optimal subgroup and duration of extended endocrine therapy is not clear yet. The aim of this study using the IDEAL patient cohort was to identify a subgroup for which longer (5 years) extended therapy is beneficial over shorter (2.5 years) extended endocrine therapy. METHODS: In the IDEAL trial, 1824 patients who completed 5 years of adjuvant endocrine therapy (either 5 years of tamoxifen (12%), 5 years of an AI (29%), or a sequential strategy of both (59%)) were randomized between either 2.5 or 5 years of extended letrozole. For each prior therapy subgroup, the value of longer therapy was assessed for both node-negative and node-positive patients using Kaplan Meier and Cox regression survival analyses. RESULTS: In node-positive patients, there was a significant benefit of 5 years (over 2.5 years) of extended therapy (disease-free survival (DFS) HR 0.67, p = 0.03, 95% CI 0.47-0.96). This effect was only observed in patients who were treated initially with a sequential scheme (DFS HR 0.60, p = 0.03, 95% CI 0.38-0.95). In all other subgroups, there was no significant benefit of longer extended therapy. Similar results were found in patients who were randomized for their initial adjuvant therapy in the TEAM trial (DFS HR 0.37, p = 0.07, 95% CI 0.13-1.06), although this additional analysis was underpowered for definite conclusions. CONCLUSIONS: This study suggests that node-positive patients could benefit from longer extended endocrine therapy, although this effect appears isolated to patients treated with sequential endocrine therapy during the first 5 years and needs validation and long-term follow-up.

5 Clinical Trial Optimal Duration of Extended Adjuvant Endocrine Therapy for Early Breast Cancer; Results of the IDEAL Trial (BOOG 2006-05). 2018

Blok, Erik J / Kroep, Judith R / Meershoek-Klein Kranenbarg, Elma / Duijm-de Carpentier, Marjolijn / Putter, Hein / van den Bosch, Joan / Maartense, Eduard / van Leeuwen-Stok, A Elise / Liefers, Gerrit-Jan / Nortier, Johan W R / Rutgers, Emiel J Th / van de Velde, Cornelis J H / Anonymous22260919. ·Departments of Surgery, Medical Oncology, and Medical Statistics, Leiden University Medical Center, Leiden, Netherlands; Department of Internal Medicine, Albert Schweitzer Hospital, Dordrecht, the Netherlands; Department of Internal Medicine, Reinier de Graaff Hospital, Delft, the Netherlands; Dutch Breast Cancer Research Group, Amsterdam, the Netherlands; Department of Surgery, Netherlands Cancer Institute, Amsterdam, the Netherlands. ·J Natl Cancer Inst · Pubmed #28922787.

ABSTRACT: Background: The optimal duration of extended endocrine therapy beyond five years after initial aromatase inhibitor-based adjuvant therapy for postmenopausal women with hormone receptor-positive breast cancer is still unknown. Therefore, we conducted a clinical trial to compare two different extended endocrine therapy durations. Methods: In the randomized phase III IDEAL trial, postmenopausal patients with hormone receptor-positive breast cancer were randomly allocated to either 2.5 or five years of letrozole after the initial five years of any endocrine therapy. The primary end point was disease free survival (DFS), and secondary end points were overall survival (OS), distant metastasis-free interval (DMFi), new primary breast cancer, and safety. Hazard ratios (HRs) were determined using Cox regression analysis. All analyses were by intention-to-treat principle. Results: A total of 1824 patients were assigned to either 2.5 years (n = 909) or five years (n = 915) of letrozole, with a median follow-up of 6.6 years. A DFS event occurred in 152 patients in the five-year group, compared with 163 patients in the 2.5-year group (HR = 0.92, 95% confidence interval [CI] = 0.74 to 1.16). OS (HR = 1.04, 95% CI = 0.78 to 1.38) and DMFi (HR = 1.06, 95% CI = 0.78 to 1.45) were not different between both groups. A reduction in occurrence of second primary breast cancer was observed with five years of treatment (HR = 0.39, 95% CI = 0.19 to 0.81). Subgroup analysis did not identify patients who benefit from five-year extended therapy. Conclusion: This study showed no superiority of five years over 2.5 years of extended adjuvant letrozole after an initial five years of adjuvant endocrine therapy.

6 Clinical Trial Adjuvant tamoxifen and exemestane in women with postmenopausal early breast cancer (TEAM): 10-year follow-up of a multicentre, open-label, randomised, phase 3 trial. 2017

Derks, Marloes G M / Blok, Erik J / Seynaeve, Caroline / Nortier, Johan W R / Kranenbarg, Elma Meershoek-Klein / Liefers, Gerrit-Jan / Putter, Hein / Kroep, Judith R / Rea, Daniel / Hasenburg, Annette / Markopoulos, Christos / Paridaens, Robert / Smeets, Jan B E / Dirix, Luc Y / van de Velde, Cornelis J H. ·Department of Surgery, Leiden University Medical Center, Leiden, Netherlands. · Department of Surgery, Leiden University Medical Center, Leiden, Netherlands; Department of Medical Oncology, Leiden University Medical Center, Leiden, Netherlands. · Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, Netherlands. · Department of Medical Oncology, Leiden University Medical Center, Leiden, Netherlands. · Department of Medical Statistics, Leiden University Medical Center, Leiden, Netherlands. · Department of Medical Oncology, University of Birmingham, Birmingham, UK. · Department of Obstetrics and Gynaecology, University Hospital Mainz, Mainz, Germany. · Department of Surgery, Medical School, National and Kapodistrian University of Athens, Athens, Greece. · University Hospital Gasthuisberg, Leuven, Belgium. · Oncology Consultancy, Loon op Zand, Netherlands. · Oncology Center, Sint-Augustinus, Wilrijk-Antwerp, Belgium. · Department of Surgery, Leiden University Medical Center, Leiden, Netherlands. Electronic address: c.j.h.van_de_velde@lumc.nl. ·Lancet Oncol · Pubmed #28732650.

ABSTRACT: BACKGROUND: After 5 years of median follow-up, the Tamoxifen Exemestane Adjuvant Multinational (TEAM) trial reported no difference in disease-free survival between exemestane monotherapy and a sequential scheme of tamoxifen followed by exemestane in postmenopausal patients with early-stage, hormone receptor-positive breast cancer. As recurrence risk in hormone receptor-positive breast cancer remains linear beyond 5 years after diagnosis, we analysed long-term follow-up outcomes of this trial. METHODS: The TEAM trial, a multicentre, open-label, randomised, controlled, phase 3 trial, included postmenopausal patients with early-stage hormone receptor-positive breast cancer from nine countries. Patients were randomly allocated (1:1) by a computer-generated random permuted block method (block sizes 4-8) to either 5 years of oral exemestane monotherapy (25 mg once a day) or a sequential scheme of oral tamoxifen (20 mg once a day) followed by exemestane for a total duration of 5 years. After the publication of the IES trial, the protocol was amended (Dec 13, 2004). Patients assigned to tamoxifen were switched after 2·5-3·0 years to exemestane therapy for a total duration of 5·0 years of treatment. Randomisation was done centrally in each country. Long-term follow-up data for disease recurrence and survival was collected in six participating countries and analysed by intention to treat. The primary endpoint was disease-free survival at 10 years of follow-up. The trial is registered with ClinicalTrials.gov, numbers NCT00279448 and NCT00032136; with Netherlands Trial Register, number NTR 267; and the Ethics Commission Trial, number 27/2001. FINDINGS: 6120 patients of the original 9776 patients in the TEAM trial were included in the current intention-to-treat analysis. Median follow-up was 9·8 years (IQR 8·0-10·3). During follow-up, 921 (30%) of 3075 patients in the exemestane group and 929 (31%) of 3045 patients in the sequential group had a disease-free survival event. Disease-free survival at 10 years was 67% (95% CI 65-69) for the exemestane group and 67% (65-69) for the sequential group (hazard ratio 0·96, 0·88-1·05; p=0·39). INTERPRETATION: The long-term findings of the TEAM trial confirm that both exemestane alone and sequential treatment with tamoxifen followed by exemestane are reasonable options as adjuvant endocrine therapy in postmenopausal patients with hormone receptor-positive early breast cancer. These results suggest that the opportunity to individualise adjuvant endocrine strategy accordingly, based on patient preferences, comorbidities, and tolerability might be possible. FUNDING: Pfizer, Dutch Cancer Foundation.

7 Article Cancer-immune interactions in ER-positive breast cancers: PI3K pathway alterations and tumor-infiltrating lymphocytes. 2019

Sobral-Leite, Marcelo / Salomon, Izhar / Opdam, Mark / Kruger, Dinja T / Beelen, Karin J / van der Noort, Vincent / van Vlierberghe, Ronald L P / Blok, Erik J / Giardiello, Daniele / Sanders, Joyce / Van de Vijver, Koen / Horlings, Hugo M / Kuppen, Peter J K / Linn, Sabine C / Schmidt, Marjanka K / Kok, Marleen. ·Division of Molecular Pathology, Netherlands Cancer Institute, Amsterdam, The Netherlands. · Coordenação de Pesquisa, Instituto Nacional do Câncer, Rio de Janeiro, RJ, Brazil. · Department of Medical Oncology, VU University Medical Centre, Amsterdam, The Netherlands. · Division of Medical Oncology, Reinier de Graaf Hospital, Delft, The Netherlands. · Department of Biometrics, Netherlands Cancer Institute, Amsterdam, The Netherlands. · Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands. · Department of Medical Oncology, Leiden University Medical Centre, Leiden, The Netherlands. · Division of Pathology, Netherlands Cancer Institute, Amsterdam, The Netherlands. · Department of Pathology, Netherlands Cancer Institute, Amsterdam, The Netherlands. · Department of Pathology, Ghent University Hospital, Ghent, Belgium. · Division of Medical Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands. · Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands. · Division of Medical Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands. m.kok@nki.nl. · Division of Molecular Oncology and Immunology, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands. m.kok@nki.nl. ·Breast Cancer Res · Pubmed #31391067.

ABSTRACT: INTRODUCTION: The presence of tumor-infiltrating lymphocytes (TILs) is correlated with good prognosis and outcome after (immuno)therapy in triple-negative and HER2-positive breast cancer. However, the role of TILs in luminal breast cancer is less clear. Emerging evidence has now demonstrated that genetic aberrations in malignant cells influence the immune landscape of tumors. Phosphatidylinositol 3-kinase (PI3K) is the most common altered pathway in ER-positive breast cancer. It is unknown whether changes in the PI3K pathway result in a different composition of the breast tumor microenvironment. Here we present the retrospective analysis of a prospective randomized trial in ER-positive breast cancer on the prognostic and predictive value of specific tumor-associated lymphocytes in the context of PI3K alterations. METHODS: We included 563 ER-positive tumors from a multicenter trial for stage I to III postmenopausal breast cancer patients, who were randomized to tamoxifen or no adjuvant therapy. The amount of CD8-, CD4-, and FOXP3-positive cells was evaluated by immunohistochemistry and quantified by imaging-analysis software. We analyzed the associations between PIK3CA hotspot mutations, PTEN expression, phosphorylated proteins of the PI3K and MAPK pathway (p-AKT, p-ERK1/2, p-4EBP1, p-p70S6K), and recurrence-free interval after adjuvant tamoxifen or no adjuvant treatment. RESULTS: CD8-positive lymphocytes were significantly more abundant in PIK3CA-mutated tumors (OR = 1.65; 95% CI 1.03-2.68). While CD4 and FOXP3 were not significantly associated with prognosis, patients with tumors classified as CD8-high had increased risk of recurrence (HR = 1.98; 95% CI 1.14-3.41; multivariable model including PIK3CA status, treatment arm, and other standard clinicopathological variables). Lymphocytes were more often present in tumors with increased PI3K downstream phosphorylation. This was most pronounced for FOXP3-positive cells. CONCLUSION: These exploratory analyses of a prospective trial in luminal breast cancer suggest high CD8 infiltration is associated with unfavorable outcome and that PI3K pathway alterations might be associated with the composition of the tumor microenvironment.

8 Article Strong CD8+ lymphocyte infiltration in combination with expression of HLA class I is associated with better tumor control in breast cancer patients treated with neoadjuvant chemotherapy. 2019

de Groot, A F / Blok, E J / Charehbili, A / Engels, C C / Smit, V T H B M / Dekker-Ensink, N G / Putter, H / Meershoek-Klein Kranenbarg, E / van de Velde, C J H / Liefers, G J / Nortier, J W R / Kuppen, P J K / van der Burg, S H / Kroep, J R. ·Department of Medical Oncology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands. · Department of Surgery, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands. · Department of Pathology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands. · Department of Statistics, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands. · Department of Medical Oncology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands. j.r.kroep@lumc.nl. ·Breast Cancer Res Treat · Pubmed #30868392.

ABSTRACT: PURPOSE: Tumor-infiltrating lymphocytes (TILs) are associated with pathological complete response (pCR) and survival after neoadjuvant chemotherapy (NAC) in patients with early breast cancer. We investigated the prognostic and predictive role of TILs, macrophages, and HLA class 1 expression after NAC with or without the potentially immune modulating compound zoledronic acid (ZA). METHODS: Baseline tumor biopsies from 196 patients in the NEOZOTAC trial were analyzed for CD8 (cytotoxic T-cells), FoxP3 (regulatory T-cells), CD68 (macrophages), and HLA class I (HCA2/HC10) expression by immunohistochemistry and subsequently related to pCR and disease-free survival (DFS). RESULTS: A strong intratumoral CD8+ infiltration or expression of HLA class 1 by cancer cells was associated with a higher pCR rate (p < 0.05). Clinical benefit of high CD8+ T-cell infiltration was found when cancer cells expressed HLA class 1 (pCR: 21.8% vs. 6.7%, p = 0.04) but not when HLA class 1 expression was lost or downregulated (pCR: 5.9% vs. 0%, p = 0.38). Interaction analyses revealed survival benefit between HLA class 1 expression and strong CD8+ T-cell infiltration, whereas in the absence or downregulation of HLA class 1 expression, high levels of CD8+ T-cells were associated with survival disadvantage (p for interaction 0.01; hazard ratio 0.41, 95% CI 0.15-1.10, p = 0.08 and hazard ratio 7.67, 95% CI 0.88-66.4, p = 0.07, respectively). Baseline immune markers were not related to ZA treatment. CONCLUSIONS: Strong baseline tumor infiltration with CD8+ T-cells in the presence of tumoral HLA class 1 expression in patients with HER2-negative breast cancer is related to a higher pCR rate and a better DFS after NAC.

9 Article Exploration of tumour-infiltrating lymphocytes as a predictive biomarker for adjuvant endocrine therapy in early breast cancer. 2018

Blok, Erik J / Engels, Charla C / Dekker-Ensink, Geeske / Meershoek-Klein Kranenbarg, Elma / Putter, Hein / Smit, Vincent T H B M / Liefers, Gerrit-Jan / Morden, James P / Bliss, Judith M / Coombes, R Charles / Bartlett, John M S / Kroep, Judith R / van de Velde, Cornelis J H / Kuppen, Peter J K. ·Department of Surgery, Leiden University Medical Center, P.O. Box 9600, 2300 RC, Leiden, The Netherlands. · Department of Medical Oncology, Leiden University Medical Center, Leiden, The Netherlands. · Department of Medical Statistics, Leiden University Medical Center, Leiden, The Netherlands. · Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands. · Clinical Trials & Statistics Unit, The Institute of Cancer Research, London, UK. · Department of Surgery & Cancer, Imperial College, London, UK. · Ontario Institute for Cancer Research, MaRS Centre, Toronto, Canada. · Department of Surgery, Leiden University Medical Center, P.O. Box 9600, 2300 RC, Leiden, The Netherlands. p.j.k.kuppen@lumc.nl. ·Breast Cancer Res Treat · Pubmed #29766362.

ABSTRACT: PURPOSE: Tumour-infiltrating lymphocytes (TILs) have been shown to be prognostic for disease-free survival and predictive for the benefit of chemotherapy in patients with early breast cancer, but have not been studied for endocrine therapy. EXPERIMENTAL DESIGN: The number of CD8-positive TILs was assessed in a subcohort of 236 patients in the Intergroup Exemestane Study. AQ After 2-3 years of adjuvant tamoxifen, AQpatients were randomized between the schemes of continuation for 5 years on tamoxifen and switching to exemestane. The numbers of CD8-positive TILs were analysed for correlations with disease-free survival (DFS) and overall survival (OS). A similar analysis was performed on 2596 patients in the TEAM trial who were randomized between the sequential scheme and the exemestane monotherapy. RESULTS: In the first cohort, patients with low (below median) numbers of CD8-positive TILs had a univariate hazard ratio (HR) for DFS of 0.27 (95% CI 0.13-0.55) in favour of treatment with exemestane, whereas this benefit was not observed in patients with high numbers of CD8-positive TILs (HR 1.34, 95% CI 0.71-2.50, HR for interaction 5.02, p = 0.001). In the second cohort, patients with low numbers of CD8-positive TILs showed a benefit of exemestane treatment on recurrence-free survival (RFS HR 0.67, 95% CI 0.45-0.99), and not with above-median numbers of CD8-positive TILs (HR 0.86, 95% CI 0.59-1.26, HR for interaction 1.29, p = 0.36). CONCLUSIONS: This study is the first to propose the number of CD8-positive TILs as potential predictive markers for endocrine therapy, with the low presence of CD8-positive TILs associated to benefit for exemestane-inclusive therapy. However, treatment-by-marker interactions were only significant in one cohort, indicating the need for further validation.

10 Article Combined evaluation of the FAS cell surface death receptor and CD8+ tumor infiltrating lymphocytes as a prognostic biomarker in breast cancer. 2017

Blok, Erik J / van den Bulk, Jitske / Dekker-Ensink, N Geeske / Derr, Remco / Kanters, Corné / Bastiaannet, Esther / Kroep, Judith R / van de Velde, Cornelis J H / Kuppen, Peter J K. ·Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands. · Department of Medical Oncology, Leiden University Medical Center, Leiden, The Netherlands. ·Oncotarget · Pubmed #28121628.

ABSTRACT: Multiple studies showed the prognostic capacities of tumor-infiltrating lymphocytes (TILs) in triple-negative breast cancer (TNBC), but not in other subtypes. We evaluated tumor expression of FAS, a key receptor in T-cell mediated apoptosis, as possible explanation for this differential prognostic value of TILs. Furthermore, we evaluated the prognostic relevance of FAS, both as an independent biomarker and in relation to CD8-positive T-cell presence. The study cohort consisted of 667 breast cancer patients treated in the LUMC between 1997 and 2009. FAS expression was determined using immunohistochemistry and the percentage of FAS-positive tumor cells was quantified. Furthermore, the number of CD8-positive infiltrating cells was determined, and its prognostic relevance was associated to FAS-expression using stratified survival analysis. In TNBC, FAS was averagely expressed in 49% of tumor cells, whereas ER-positive subtypes showed an average Fas expression of 16-20%. In the entire cohort, FAS was identified as significant prognostic marker for recurrence (adjusted HR 0.53, 95% CI 0.36-0.77) and borderline significant marker for overall survival (adjusted HR 0.72, 95% CI 0.52-1.01). Upon stratification for FAS-expression, CD8+ TILs were only prognostic at high levels (above median) of FAS expression in ER-negative disease. In summary, FAS was identified as an independent prognostic marker for recurrence free survival in breast cancer, with large variation in expression by receptor subtypes. Interestingly, the prognostic effect of CD8+ TILs in ER-negative disease was only valid for tumors with a high FAS expression.

11 Minor 70-Gene Signature in Early-Stage Breast Cancer. 2016

Blok, Erik J / van de Velde, Cornelis J / Smit, Vincent T. ·Leiden University Medical Center, Leiden, the Netherlands v.t.h.b.m.smit@lumc.nl. ·N Engl J Med · Pubmed #27959763.

ABSTRACT: -- No abstract --