Johanna G H van Nes

Publications (10)45.22 Total impact

• Article: Influence of semi-quantitative oestrogen receptor expression on adjuvant endocrine therapy efficacy in ductal and lobular breast cancer - A TEAM study analysis.

  Willemien van de Water, Duveken B Y Fontein, Johanna G H van Nes, John M S Bartlett, Elysée T M Hille, Hein Putter, Tammy Robson, Gerrit-Jan Liefers, Rudi M H Roumen, Caroline Seynaeve, Luc Y Dirix, Robert Paridaens, Elma Meershoek-Klein Kranenbarg, Johan W R Nortier, Cornelis J H van de Velde
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  ABSTRACT: BACKGROUND: Multiple studies suggest better efficacy of chemotherapy in invasive ductal breast carcinomas (IDC) than invasive lobular breast carcinomas (ILC). However, data on efficacy of adjuvant endocrine therapy regimens and histological subtypes are sparse. This study assessed endocrine therapy efficacy in IDC and ILC. The influence of semi-quantitative oestrogen receptor (ER) expression by Allred score was also investigated. METHODS: Dutch and Belgian patients enrolled in the Tamoxifen Exemestane Adjuvant Multinational (TEAM) trial were randomized to exemestane (25mg daily) alone or following tamoxifen (20mg daily) for 5years. Inclusion was restricted to IDC and ILC patients. Histological subtype was assessed locally; ER expression was centrally reviewed according to Allred score (ER-poor (<7; n=235); ER-rich (⩾7; n=1789)). Primary end-point was relapse-free survival (RFS), which was the time from randomization to disease relapse. FINDINGS: Overall, 2140 (82%) IDC and 463 (18%) ILC patients were included. RFS was similar for both endocrine treatment regimens in IDC (hazard ratio (HR) for exemestane was 0.83 (95%confidence interval (CI) 0.67-1.03)), and ILC (HR 0.69 (95%CI 0.45-1.06)). Irrespective of histological subtype, patients with ER-rich Allred scores allocated to exemestane alone had an improved RFS (multivariable HR 0.71 (95%CI 0.56-0.89)). In contrast, patients with ER-poor Allred scores allocated to exemestane had a worse RFS (multivariable HR 2.33 (95%CI 1.32-4.11)). Significant effect modification by ER-Allred score was confirmed (multivariable p=0.003). INTERPRETATION: Efficacy of endocrine therapy regimens was similar for IDC and ILC. However, ER-rich patients showed superior efficacy to upfront exemestane, while ER-poor patients had better outcomes with sequential therapy, irrespective of histological subtype, emphasising the relevance of quantification of ER expression. FUNDING: The Dutch/Belgian TEAM trial is supported by an unrestricted research grant from Pfizer. The sponsors have in no way influenced the design and conduct of the study, collection, management, analysis and interpretation of the data and preparation, review or approval of the manuscript.
  European journal of cancer (Oxford, England: 1990) 09/2012; · 4.12 Impact Factor
• Article: Hypomethylation of LINE-1 in primary tumor has poor prognosis in young breast cancer patients: a retrospective cohort study.

  Anneke Q van Hoesel, Cornelis J H van de Velde, Peter J K Kuppen, Gerrit Jan Liefers, Hein Putter, Yusuke Sato, David A Elashoff, Roderick R Turner, Jaime M Shamonki, Esther M de Kruijf, Johanna G H van Nes, Armando E Giuliano, Dave S B Hoon
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  ABSTRACT: Long interspersed element 1 (LINE-1), a non-coding genomic repeat sequence, methylation status can influence tumor progression. In this study, the clinical significance of LINE-1 methylation status was assessed in primary breast cancer in young versus old breast cancer patients. LINE-1 methylation index (MI) was assessed by absolute quantitative assessment of methylated alleles (AQAMA) PCR assay. Initially, LINE-1 MI was assessed in a preliminary study of 235 tissues representing different stages of ductal breast cancer development. Next, an independent cohort of 379 primary ductal breast cancer patients (median follow-up 18.9 years) was studied. LINE-1 hypomethylation was shown to occur in DCIS and invasive breast cancer. In primary breast cancer it was associated with pathological tumor stage (p = 0.026), lymph node metastasis (p = 0.022), and higher age at diagnosis (>55, p < 0.001). In multivariate analysis, LINE-1 hypomethylation was associated with decreased OS (HR 2.19, 95 % CI 1.17-4.09, log-rank p = 0.014), DFS (HR 2.05, 95 % CI 1.14-3.67, log-rank p = 0.016) and increased DR (HR 2.83, 95 % CI 1.53-5.21, log-rank p = 0.001) in younger (≤55 years), but not older patients (>55 years). LINE-1 analysis of primary breast cancer demonstrated cancer-related age-dependent hypomethylation. In patients ≤55 years, LINE-1 hypomethylation portends a high-risk of DR.
  Breast Cancer Research and Treatment 04/2012; 134(3):1103-14. · 4.43 Impact Factor
• Source

  Available from: Alison F Munro

  Article: Co-expression of SNAIL and TWIST determines prognosis in estrogen receptor-positive early breast cancer patients.

  Johanna G H van Nes, Esther M de Kruijf, Hein Putter, Dana Faratian, Alison Munro, Fiona Campbell, Vincent T H B M Smit, Gerrit-Jan Liefers, Peter J K Kuppen, Cornelis J H van de Velde, John M S Bartlett
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  ABSTRACT: Epithelial mesenchymal transition (EMT) plays an important role in the development of metastases. One of the hallmarks of EMT is loss of E-cadherin and gain of N-cadherin expression, which are regulated by transcription factors, such as SNAIL, SLUG, and TWIST. We examined the prognostic value of these factors as well as E-cadherin and N-cadherin, in a well-described large cohort of breast cancer patients treated with primary surgery. Analyses were stratified by estrogen receptor (ER) status, because of its crucial role in the regulation of these transcription factors. SNAIL, SLUG, and TWIST expression were examined on a TMA containing 575 breast tumors using immunohistochemistry. Nuclear expression was quantified using a weighted histoscore and classified as high versus low expression, based on the median histoscore. High expression of SNAIL, SLUG, and TWIST was seen in 54, 50, and 50% of tumors, respectively. The level of SNAIL (P = 0.014) and TWIST (P = 0.006) expression was associated with a worse patient relapse-free period, specifically in patients with ER-positive tumors (interaction Cox proportional hazards P = 0.039). Combining both factors resulted in an independent prognostic factor with high discriminative power (both low versus either high: HR 1.15; both low versus both high HR 1.84; P = 0.010). Co-expression of SNAIL-TWIST was associated with low-E-cadherin and high-N-cadherin expression, especially in ER-positive tumors (P = 0.009), suggesting that, through interactions with ER, SNAIL and TWIST may regulate E- and N-cadherin expression, thereby inducing EMT. Our results are indicative that SNAIL and TWIST play a crucial role in EMT through regulation of E- and N-cadherin expression, exclusively in ER-positive breast cancer patients.
  Breast Cancer Research and Treatment 07/2011; 133(1):49-59. · 4.43 Impact Factor
• Article: The effect of exemestane and tamoxifen on bone health within the Tamoxifen Exemestane Adjuvant Multinational (TEAM) trial: a meta-analysis of the US, German, Netherlands, and Belgium sub-studies.

  Peyman Hadji, Lina Asmar, Johanna G H van Nes, Thomas Menschik, Annette Hasenburg, Joachim Kuck, Johan W R Nortier, Cornelis J H van de Velde, Stephen E Jones, May Ziller
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  ABSTRACT: We performed a meta-analysis of three sub-studies of the randomized Tamoxifen Exemestane Adjuvant Multinational (TEAM) trial to determine the effects of exemestane and tamoxifen on bone health. Patients received exemestane or tamoxifen as adjuvant therapy for hormone receptor-positive breast cancer. Bone mineral density (BMD) was assessed at baseline and after 12 and 24 months of treatment. Bone turnover markers were also measured. Patients receiving tamoxifen showed a mean increase from baseline in lumbar spine BMD of 1.2% at month 12 and 0.2% at month 24. Patients receiving exemestane showed a mean decrease from baseline of 2.6% after 12 months and 3.5% after 24 months. There were significant differences in the changes in lumbar spine BMD between treatment groups (P < 0.0001 at both time points). Changes in BMD from baseline at the total hip were also significantly different between exemestane and tamoxifen (P < 0.05 at both time points). Bone turnover markers decreased from baseline with tamoxifen and increased with exemestane. Exemestane resulted in decreases in BMD and increases in bone turnover markers. BMD increased and bone turnover markers decreased with tamoxifen.
  Journal of Cancer Research and Clinical Oncology 06/2011; 137(6):1015-25. · 2.56 Impact Factor
• Article: Primary tumor classification according to methylation pattern is prognostic in patients with early stage ER-negative breast cancer.

  Anneke Q van Hoesel, Cornelis J H van de Velde, Peter J K Kuppen, Hein Putter, Esther M de Kruijf, Johanna G H van Nes, Armando E Giuliano, Dave S B Hoon
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  ABSTRACT: Breast cancer patients with similar clinical stage may experience different disease outcomes. Aberrant DNA methylation of primary breast tumors can have impact on the clinical outcome. This study aimed to assess clinical utility of tumor-specific methylated sequences (MINT17, 31) and tumor-related gene (RARβ2) methylation classification in primary breast tumors. Absolute quantitative assessment of methylated alleles (AQAMA) was used to determine the methylation index (MI) of MINT17, MINT31, and RARß2 in 242 primary tumors of early stage breast cancer patients. Patients were classified into three methylation groups: meth-N, with normal methylation levels of all biomarkers; meth-L, with one biomarker hypermethylation; and meth-H, with hypermethylation of >1 biomarker. Disease outcome of methylation groups was compared during follow-up. MI of all biomarkers was successfully obtained in 237 tumors of which 79 (33%) were classified as meth-N, 86 (36%) as meth-L, and 72 (30%) as meth-H. Meth-H status was a risk factor for distant recurrence (DR) (log-rank P = 0.007) and shorter disease-free survival (DFS) (log-rank P = 0.039). Methylation classification had strongest prognostic value for patients with ER-negative tumors. In multivariate analysis (n = 222), ER-negative meth-H patients had a 4.1-fold increased risk of DR (95% CI 1.80-9.59; meth-N HR 1.0, P = 0.001), a 4.2-fold increased risk of overall recurrence (OR) (95% CI 1.88-9.47; meth-N HR 1.0, P = 0.001), and a 3.1-fold shorter DFS (95% CI 1.57-5.98; meth-N HR 1.0, P = 0.003). Methylation classification of primary breast cancer is an independent prognostic factor for disease outcome in patients with ER-negative tumors. The study's findings will have to be confirmed in an independent dataset.
  Breast Cancer Research and Treatment 04/2011; 131(3):859-69. · 4.43 Impact Factor
• Article: HLA-E and HLA-G expression in classical HLA class I-negative tumors is of prognostic value for clinical outcome of early breast cancer patients.

  Esther M de Kruijf, Anita Sajet, Johanna G H van Nes, Russ Natanov, Hein Putter, Vincent T H B M Smit, Gerrit Jan Liefers, Peter J van den Elsen, Cornelis J H van de Velde, Peter J K Kuppen
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  ABSTRACT: Nonclassical HLAs, HLA-E and HLA-G, are known to affect clinical outcome in various tumor types. We examined the clinical impact of HLA-E and HLA-G expression in early breast cancer patients, and related the results to tumor expression of classical HLA class I. Our study population (n = 677) consisted of all early breast cancer patients primarily treated with surgery in our center between 1985 and 1995. Tissue microarray sections of arrayed tumor and normal control material were immunohistochemically stained for HLA-E and HLA-G. For evaluation of HLA-E and HLA-G and the combined variable, HLA-EG, a binary score was used. Expression of classical HLA class I molecules was determined previously. HLA-E, HLA-G, and HLA-EG on breast tumors were classified as expression in 50, 60, and 23% of patients, respectively. Remarkably, only in patients with loss of classical HLA class I tumor expression, expression of HLA-E (p = 0.027), HLA-G (p = 0.035), or HLA-EG (p = 0.001) resulted in a worse relapse-free period. An interaction was found between classical and nonclassical HLA class I expression (p = 0.002), suggestive for a biological connection. We have demonstrated that, next to expression of classical HLA class I, expression of HLA-E and HLA-G is an important factor in the prediction of outcome of breast cancer patients. These results provide further evidence that breast cancer is immunogenic, but also capable of evading tumor eradication by the host's immune system, by up- or downregulation of HLA class Ia and class Ib loci.
  The Journal of Immunology 11/2010; 185(12):7452-9. · 5.79 Impact Factor
• Source

  Available from: Peter J.K. Kuppen

  Article: Tumor-stroma ratio in the primary tumor is a prognostic factor in early breast cancer patients, especially in triple-negative carcinoma patients.

  Esther M de Kruijf, Johanna G H van Nes, Cornelis J H van de Velde, Hein Putter, Vincent T H B M Smit, Gerrit Jan Liefers, Peter J K Kuppen, Rob A E M Tollenaar, Wilma E Mesker
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  ABSTRACT: Stroma tissue surrounding cancer cells plays an important role in tumor development and behavior. In colorectal cancer, it has been found that the amount of stroma within the primary tumor is of prognostic value. We therefore have evaluated the prognostic value of this tumor-stroma ratio for breast cancer. A cohort of 574 early breast cancer patients, primarily treated with surgery between 1985 and 1994 was analyzed for the tumor-stroma ratio. The percentage of stroma was visually estimated on Haematoxylin-Eosin (H&E) stained histological sections. Patients with more than 50% intra-tumor stroma were quantified as stroma rich and patients with less than 50% as stroma poor. For the total group of patients, stroma-rich tumors had a shorter relapse-free period (RFP) (P = 0.001) and overall survival (OS) (P = 0.025) compared to stroma-poor tumors. Tumor-stroma ratio was an independent prognostic parameter for the total group of patients (P < 0.001) and also in stratified analysis based on systemic treatment. Importantly, in the triple-negative cancer subpopulation, patients with stroma-rich tumors had a 2.92 times higher risk of relapse (P = 0.006) compared to those with stroma-poor tumors, independently of other clinico-pathological parameters. Five-year RFP-rates for triple-negative cancer patients with stroma-rich compared to stroma-poor tumors were 56 and 81%, respectively. Tumor-stroma ratio has proven to be an independent prognostic factor for RFP in breast cancer patients and especially in the triple-negative cancer subpopulation. Tumor-stroma ratio could be easily implemented in routine daily pathology diagnostics, as it is simple to determine, reproducible, and performed in quick time.
  Breast Cancer Research and Treatment 04/2010; 125(3):687-96. · 4.43 Impact Factor
• Source

  Available from: Peter J.K. Kuppen

  Article: COX2 expression in prognosis and in prediction to endocrine therapy in early breast cancer patients.

  Johanna G H van Nes, Esther M de Kruijf, Dana Faratian, Cornelis J H van de Velde, Hein Putter, Claire Falconer, Vincent T H B M Smit, Charlene Kay, Marc J van de Vijver, Peter J K Kuppen, John M S Bartlett
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  ABSTRACT: In breast cancer, the prognostic impact of COX2 expression varies widely between studies. We examined the prognostic value of COX2 expression in a large cohort of breast cancer patients treated with primary surgery between 1985 and 1994 and explained the variable results of COX2 expression found in the literature. A tissue microarray was constructed of available tumour material, and ER, PgR, HER2, Ki67 and COX2 were examined by immunohistochemistry. Median follow-up was 19 years. Fifty-five percent (n = 369/677) of patients received no systemic treatment. COX2 was scored using a weighted histoscore. Analysis of COX2 expression in two groups based on the median (148; below vs. above) showed an increased hazard ratio (HR) of 1.35 (95% CI 1.05-1.75, P = 0.021) for disease-free survival (DFS) and of 1.39 (95% CI 1.03-1.82, P = 0.016) for overall survival (OS). However, COX2 did not remain independent in multivariate analysis. In patients with hormone receptor positive tumours, COX2 expression had a negative influence on outcome (low vs. high: DFS: HR 1.37, 95% CI 1.07-1.76, P = 0.013). This effect disappeared when endocrine therapy was administered (low vs. high: DFS: HR 0.93, 95% CI 0.51-1.70, P = 0.811) while it remained statistically significant when endocrine therapy was omitted (low vs. high: DFS: HR 1.48, 95% CI 1.12-1.94, P = 0.005). Our results show that COX2 plays a role in hormonal pathways. Our results can explain the results found in previously published studies.
  Breast Cancer Research and Treatment 04/2010; 125(3):671-85. · 4.43 Impact Factor
• Article: The predictive value of HLA class I tumor cell expression and presence of intratumoral Tregs for chemotherapy in patients with early breast cancer.

  Esther M de Kruijf, Johanna G H van Nes, Anita Sajet, Quirijn R J G Tummers, Hein Putter, Susanne Osanto, Frank M Speetjens, Vincent T H B M Smit, Gerrit Jan Liefers, Cornelis J H van de Velde, Peter J K Kuppen
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  ABSTRACT: We hypothesized that T-cell immune interaction affects tumor development and thus clinical outcome. Therefore, we examined the clinical impact of human leukocyte antigen (HLA) class I tumor cell expression and regulatory T-cell (Treg) infiltration in breast cancer. Our study population (N = 677) is consisted of all early breast cancer patients primarily treated with surgery in our center between 1985 and 1994. Formalin-fixed, paraffin-embedded tumor tissue was immunohistochemically stained using HCA2, HC10, and Foxp3 monoclonal antibodies. HLA class I expression was evaluated by combining results from HCA2 and HC10 antibodies and classified into three groups: loss, downregulation, and expression. Remarkably, only in patients who received chemotherapy, both presence of Treg (P = 0.013) and higher HLA class I expression levels (P = 0.002) resulted in less relapses, independently of other variables. Treg and HLA class I were not of influence on clinical outcome in patients who did not receive chemotherapy. We showed that HLA class I and Treg affect prognosis exclusively in chemotherapy-treated patients and are therefore one of the few predictive factors for chemotherapy response in early breast cancer patients. Chemotherapy may selectively eliminate Treg, thus enabling CTLs to kill tumor cells that have retained HLA class I expression. As a consequence, HLA class I and Treg can predict response to chemotherapy with high discriminative power. These markers could be applied in response prediction to chemotherapy in breast cancer patients.
  Clinical Cancer Research 02/2010; 16(4):1272-80. · 7.74 Impact Factor
• Article: Endoscopic aneurysm sac fenestration as a treatment option for growing aneurysms due to type II endoleak or endotension.

  Johanna G H van Nes, Johanna M Hendriks, Larissa N L Tseng, Lukas C van Dijk, Marc R H M van Sambeek
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  ABSTRACT: To evaluate endoscopic fenestration as a treatment option for growing aneurysm due to a type II endoleak or endotension after endovascular aneurysm repair (EVAR). Eight patients (7 men; median age 69 years, range 55-79) who underwent "successful" EVAR were diagnosed with a growing aneurysm due to a type II endoleak (n=4) or endotension (n=4). Surgical intervention consisted of endoscopic fenestration of the sac and removal of all the thrombus material, preceded by clipping of the inferior mesenteric and all lumbar arteries in cases of endoleak. Fluid samples from the fenestrated aneurysm sac were analyzed for the presence of microorganisms and fibrin degradation products (FDP) and/or D-dimers. The median duration of operation was 220 minutes (range 111-333). There was no perioperative mortality. In one patient, the endoscopic procedure was converted to an open fenestration procedure. Seven patients had uncomplicated follow-up and a clear decrease in the diameter of the sac; one patient was converted to open repair owing to continued sac growth despite fenestration. Bacterial cultures were negative in all patients, but high levels of FDP and/or D-dimers were found in all available samples, indicating continued fibrinolysis. Endoscopic fenestration, with or without endoscopic clipping of all side branches, seems to be an effective, reliable and minimally invasive treatment option for patients with a growing aneurysm due to type II endoleak or endotension. The high levels of FDP and/or D-dimers in the aneurysm sac are suggestive of hyperfibrinolysis, which may play an important role in aneurysm growth after EVAR.
  Journal of Endovascular Therapy 09/2005; 12(4):430-4. · 2.86 Impact Factor