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Aim: To investigate the role of optoacoustic imaging combined with gray-scale ultrasound (OA/US) to better differentiate between breast cancer molecular subtypes. Materials and Methods: This prospective 5-center study was performed in the Netherlands between March 2015 and February 2016. Only masses considered suspicious at conventional diagnostic breast ultrasound (US) were included. The study was approved by the institutional ethical boards of the participating hospitals and written informed consent was obtained from all patients. Dedicated breast radiologists evaluated the included masses using OA/US and scored the internal and external OA/US features accordingly. Spearman Correlation was used to analyze the relationship between OA/US features and mitotic figures. The same statistical method was also used to evaluate the correlation between OA/US features and percentages of ER, PR and Ki67. Wilcoxon-Mann-Whitney tests were used to analyze the relationship between OA/US features and molecular subtypes of breast cancer (Luminal A, Luminal B, Triple Negative and HER2-enriched breast cancers). Results: Overall, 209 patients with 215 breast lesions were included in this study. Sixty-seven masses were considered malignant and the 59 masses classified as invasive breast cancers were included in the final mitotic figures, ER, PR, Ki-67 and molecular subtype analyses. Significant correlations were found between OA/US Total Internal Features and ER (p = 0.0333) and Ki-67 (p = 0.0092) percentages. Regarding molecular subtypes, Internal Vessels (p = 0.0257), Total Internal Features (p = 0.0196) and combined Total Internal and External Features (p = 0.0289) helped to differentiate between Luminal A and Luminal B cancers. Internal Vessels (p = 0.0030), Internal Blush (p = 0.0044), Total Internal Hemoglobin (p = 0.0053), Total Internal Features (p = 0.0010), Total Internal divided by Total External Features (p=0.0255) and combined Total Internal and External Features (p = 0.0108) helped to differentiate between Luminal A and Triple Negative breast cancers. Total Internal Features showed a borderline result (p = 0.0551) regarding the differentiation between Triple Negative and HER2-enriched subtypes. Conclusions: The use of OA/US features to non-invasively differentiate between breast cancer molecular subtypes may help to establish an earlier prognosis and treatment planning, potentially decreasing costs and facilitating larger scale diagnosis. Future research with larger sample sizes may confirm these preliminary results. Citation Format: Menezes GL, Mann RM, Meeuwis C, Bisschops B, Veltman J, Lavin PT, van de Vijver MJ, Pijnappel RM. Can optoacoustic imaging combined with ultrasound non-invasively offer prognosis for breast cancer molecular subtypes? [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-08-43.

Background Epithelial-to-mesenchymal transition (EMT) has been implicated as an important step in the development of distant metastases. We therefore wished to study EMT status of primary breast carcinomas from patients who during follow-up developed distant metastases. Methods mRNA expression profiles of primary breast carcinoma samples (n = 151) from patients who developed metastatic disease were analyzed and EMT status was designated using a previously described EMT-core signature. EMT status of the primary tumor was correlated to clinicopathological characteristics, molecular subtypes, metastasis pattern, chemotherapy response and survival outcomes. In addition, using immunohistochemistry, the expression levels of several proteins implicated in EMT were studied (CDH1, CDH2, NAT1, SNAI2, TWIST1, VIM, and ZEB1) compared with the designated EMT status and survival. Results Utilizing the 130-gene-EMT-core signature, 66.2% of the primary tumors in the current study was assessed as EMT-activated. In contrast to our expectations, analyses revealed that 84.6% of Luminal A tumors, 65.1% of Luminal B tumors, and 55.6% of HER2-like had an activated EMT status, compared to only 25% of the basal-type tumors (p

Background The recent expanding technical possibilities to detect tumor derived mutations in blood, so-called circulating tumor DNA (ctDNA), has rapidly increased the interest in liquid biopsies. This review and meta-analysis explores the clinical value of ctDNA in malignancies of the upper gastro-intestinal tract. Methods PubMed, Cochrane and Embase databases were searched to identify studies reporting the diagnostic, prognostic or predictive value of ctDNA in patients with esophageal, gastric and pancreatic cancer, until January 2017. The diagnostic accuracy and, using random-effect pair-wise meta-analyses, the prognostic value of ctDNA was assessed. Results A total of 34 studies met the inclusion criteria. For esophageal and gastric cancer, amplification of oncogenes in blood, such as HER2 and MYC, can be relevant for diagnostic purposes, and to predict treatment response in certain patient subpopulations. Given the limited number of studies assessing the role of ctDNA in esophageal and gastric cancer, the meta-analysis estimated the diagnostic accuracy and predictive value of ctDNA in pancreatic cancer only ( n = 10). The pooled sensitivity and specificity of ctDNA as a diagnostic tool in pancreatic cancer were 28% and 95%, respectively. Patients with pancreatic cancer and detectable ctDNA demonstrated a worse overall survival compared to patients with undetectable ctDNA (HR 1.92, 95% confidence interval (CI) 1.15–3.22, p = 0.01). Conclusion The presence of ctDNA is significantly associated with a poor prognosis in patients with pancreatic cancer. The use of ctDNA in clinical practice is promising, although standardization of sequencing techniques and further development of high-sensitive detection methods is needed.

Background Visceral organ metastasis is associated with poor survival outcomes in terms of metastasis free- and overall survival in breast carcinomas. Identification of a gene expression profile in tumours that selects a subpopulation of patients that is more likely to develop visceral organ metastases will help elucidate mechanisms for the development of distant metastases and could be of clinical value. With this study we aimed to determine genomic predictors that would help to distinguish breast cancer patients with more likelihood to develop visceral metastasis. Methods Gene expression profiling data of 157 primary tumours from breast cancer patients who developed distant metastases were analyzed and differentially expressed genes between the group of tumours with visceral metastasis and the those without visceral metastases were identified. Published data were used to validate our findings. Multivariate logistic regression tests were applied to further investigate the association between the gene-expression-signature and clinical variables. Survival analyses were performed by the Kaplan-Meier method. Results Fourteen differentially expressed genes (WDR6, CDYL, ATP6V0A4, CHAD, IDUA, MYL5, PREP, RTN4IP1, BTG2, TPRG1, ABHD14A, KIF18A, S100PBP and BEND3) were identified between the group of tumours with and without visceral metastatic disease. Five of these genes (CDYL, ATP6V0A4, PREP, RTN4IP1 and KIF18A) were up-regulated and the other genes were down-regulated. This gene expression signature was validated in the training and in the independent data set (p 2.13e− 08 and p 9.68e− 06, respectively). Multivariate analyses revealed that the 14-gene-expression-signature was associated with visceral metastatic disease (p 0.001, 95% CI 1.43–4.27), independent of other clinicopathologic features. This signature has been also found to be associated with survival status of the patients (p

OBJECTIVES: Sessile serrated polyps (SSPs) are suggested to be the precursors of 15-30% of all colorectal cancers (CRCs). Therefore, CRC screening modalities should also be designed to detect high-risk SSPs. We compared computed tomography colonography (CTC) with colonoscopy-based screening for the detection of high-risk SSPs in average-risk individuals. METHODS: Data from a randomized controlled trial that compared CTC with colonoscopy for population screening were used for the analysis. Individuals diagnosed at CTC with a lesion >= 10 mm in size were referred for colonoscopy. Individuals with only 6-9 mm lesions were offered surveillance CTC. This surveillance CTC was followed by a colonoscopy when a lesion >= 6 mm was detected. Yield of both was accumulated to mimic current American College of Radiology CTC referral strategy (referral of individuals with any lesion >= 6 mm). Per participant detection of >= 1 high-risk (dysplastic and/or = 10 mm) SSP was compared with colonoscopy using multiple logistic regression analysis. RESULTS: In total, 8,844 individuals were invited to participate (in 2: 1 allocation), of which 1,276 colonoscopy and 982 CTC invitees participated in the study. In the colonoscopy arm, 4.3% of individuals were diagnosed with >= 1 high-risk SSP, compared with 0.8% in the CTC arm (odds ratio (OR) 5.5; 95% confidence interval (CI) 2.6-11.6; P

Pancreatic ductal adenocarcinoma (PDAC) is characterized by abundant stroma that harbors tumor-promoting properties. No good biomarkers exist to monitor the effect of stromal targeting therapies or to predict response. We set out to identify such non-invasive markers for PDAC stroma and predict response to therapy. Gene expression datasets, co-culture experiments, xenografts, and patient samples were analyzed. Serum samples were measured from a cohort of 58 resected patients, and 87 metastatic or locally advanced PDAC patients. Baseline and follow-up levels were assessed in 372 additional metastatic PDAC patients who received nab-paclitaxel with gemcitabine (n = 184) or gemcitabine monotherapy (n = 188) in the phase III MPACT trial. Increased levels of ADAM12 were found in PDAC patients compared to healthy controls (p n = 157 and n = 38). High levels of ADAM12 significantly associated with poor outcome in resected PDAC (HR 2.07, p = 0.04). In the MPACT trial survival was significantly longer for patients who received nab-paclitaxel and had undetectable ADAM12 levels before treatment (OS 12.3 m vs 7.9 m p = 0.0046). Consistently undetectable or decreased ADAM12 levels during treatment significantly associated with longer survival as well (OS 14.4 m and 11.2 m, respectively vs 8.3, p = 0.0054). We conclude that ADAM12 is a blood-borne proxy for stromal activation, the levels of which have prognostic significance and correlate with treatment benefit.

BACKGROUND: Locally advanced and/or inflammatory breast cancer (LABC) is a heterogeneous disease. Molecular markers may help to understand this heterogeneity. This paper reports the results of a study assessing the potential prognostic or predictive value of HER-2, p53, cyclinD1, MIB1, ER and PgR expression by immunohistochemistry from patients included in an EORTC-NCIC-SAKK trial. PATIENTS AND METHODS: A total of 448 patients with a cytological or histological diagnosis of LABC were randomised into a trial comparing two anthracycline-based neoadjuvant regimens. Chemotherapy was followed by standard locoregional therapy. Survival was comparable in both arms. We collected and analysed centrally paraffin-embedded tumour specimens from 187 (72.5%) of 258 patients that had a histological diagnosis. RESULTS: Of the patients included in this molecular marker study 114 relapsed and 91 died. In the multivariate analysis p53 positivity was associated with a shorter progression-free survival [hazard ratio (HR) = 1.96; 95% CI 1.33-2.91; P = 0.0008) and a shorter overall survival (HR = 1.98; 95% CI 1.28-3.06; P = 0.002). PgR positivity predicted for a longer overall survival (HR = 0.54; 95% CI 0.35-0.83; P = 0.0045). CONCLUSIONS: p53 was an independent factor predicting for survival. In order to clarify whether p53 is a pure prognostic and/or a predictive factor, a phase III trial is being conducted (EORTC 10994/BIG 00-01 study) using functional assay in yeast from frozen tumour samples

A comprehensive whole genome analysis of a large breast cancer cohort of 560 cases (Nik-Zainal et al, submitted 2015) reports novel and existing DNA substitution and rearrangement signatures next a comprehensive list of events driving the breast cancer cell to its malignant potency. In the current study, we linked the observed genetic diversity to the breast cancer transcriptome for 260 cases for which whole genome and whole transcriptome data were both available. Cluster analysis of the global gene expression showed the familiar view of a coherent basal-like and a heterogeneous luminal subgroup. New and previously reported1 subtype-specific aberrations with concordant expression changes were found in TP53, PIK3CA, PTEN, CCND1, CDH1 and GATA3, and mutations in PIK3CA, PTEN, AKT1 and AKT2 were mutually exclusive confirming they are active in the same pathway in breast cancer. Integrating the identified DNA substitutions signatures with the transcriptome, we observed that the total number of substitutions in a cancer, irrespective of substitution type, was positively associated with cell cycle regulated gene expression and with adverse outcome. In addition and more remarkably, we observed that the number substitution of two substitution signatures2 particularly associated with immune-response specific gene expression, with increased amount of tumor infiltrating lymphocytes and with a better outcome. These two signatures comprised 1) mutations of the APOBEC-type (predominant C>G in a TCN context), and 2) mutations which lacks specific features but which are strongly associated with genetic and epigenetic inactivating aberrations in BRCA1 and BRCA2. Thus, while earlier reports3-5 imply that the sheer number of driver events triggers an immune-response, we refine this statement by observing that substitutions of a particular type are much very effective in doing so explaining the superior outcome of cancer having these particular types of substitutions. This result also implies that purposefully augmenting T-cell reactivity against amino-acid substitutions resulting from either of these two DNA substitution types could potentially improve immunotherapies in breast cancer. 1. Comprehensive molecular portraits of human breast tumours. Nature 490, 61-70 (2012). 2. Alexandrov, L.B., et al. Signatures of mutational processes in human cancer. Nature 500, 415-421 (2013). 3. Rizvi, N.A., et al. Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 348, 124-128 (2015). 4. Schumacher, T.N. & Schreiber, R.D. Neoantigens in cancer immunotherapy. Science 348, 69-74 (2015). 5. Snyder, A., et al. Genetic basis for clinical response to CTLA-4 blockade in melanoma. N Engl J Med 371, 2189-2199 (2014). Citation Format: Martens JWM, Smid M, Rodríguez-González G, Sieuwerts AM, Prager-Van der Smissen WJC, Van Der Vlugt - Daane M, Van Galen A, Nik-Zainal S, Staaf J, Brinkman AB, Van de Vijver MJ, Richardson AL, Berentsen K, Caldas C, Butler A, Martin S, Davies HD, Debets R, Meijer-Van Gelder ME, Van Deurzen CHM, Ramakrishna MR, Ringnér M, Viari A, Birney E, Børresen-Dale A-L, Stunnenberg HG, Stratton M, Foekens JA. Mutational signatures impact the breast cancer transcriptome and distinguish mitotic from immune response pathways. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P6-08-10.

Several studies have validated the prognostic value of the 70-gene prognosis signature (MammaPrintR), but long-term outcome prediction of these patients has not been previously reported. The follow-up of the consecutively treated cohort of 295 patients (

Background Several studies have assessed the concordance of estrogen receptor (ER) and human epidermal growth factor receptor 2 (HER2) status between core needle biopsy (CNB) and resection specimens, usually in small patient series and with discordant results. Patients and methods ER and HER2 status determined on CNB and tissue micro-arrays of resected tumors were compared for patients treated at the Leiden University Medical Center (LUMC). When results were discordant, whole-sized slides were analyzed. Additionally, literature was searched for published patient series and combined with our data to assess the concordance of ER and HER2 determination between CNB and resection specimens. Results In the LUMC series, concordance for ER status was 99.1%. Combined concordance from 20 studies and the LUMC patient series was 93.7%. For HER2 testing, concordance was 96.2% for patients in the LUMC series. Our study and three others have investigated the concordance when HER2 was determined according to the American Society of Clinical Oncology and College of Pathology guidelines and overall concordance was 97.8%. Conclusions Concordance between CNB and surgical specimens was high for both ER and HER2 testing. However, we recommend retesting ER-negative CNB results on the surgical specimen and performing in situ hybridization assays on HER2 immunohistochemistry 3+ CNBs to confirm HER2 status.

Item does not contain fulltext BACKGROUND: We studied discordance in estrogen receptor alpha (ERalpha), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) status between multiple distant metastases from the same breast cancer patient. MATERIAL AND METHODS: Multiple distant metastases from 55 female patients were stained for ERalpha, PR and HER2 by immunohistochemistry and in situ hybridization for confirmation of the HER2 status. RESULTS: Different metastatic sites within the same patient showed discordance in ERalpha receptor status in 7.3% or 10.9% of patients (using a 10% or 1% threshold for positivity, respectively). For PR, 29.1% or 30.9% of patients showed discordance. Taking ERalpha and PR together, 36.4% of cases (both thresholds) showed discrepancy between metastases. In 10.9% (10% threshold) or 14.5% of patients (1% threshold), such discordance could have clinical consequences with regard to hormonal treatment. For HER2, there was 3.6% discordance on the immunohistochemical level but 0% on the gene level. CONCLUSION: In a significant proportion of metastatic breast cancer patients, discordance in ERalpha and PR receptor status between different metastatic sites was observed. This implies that multiple metastases may need to be biopsied to optimally reassess receptors.

The 70-gene signature (MammaPrint™) has been developed on retrospective series of breast cancer patients to predict the risk of breast cancer distant metastases. The microarRAy-prognoSTics-in-breast-cancER (RASTER) study was the first study designed to prospectively evaluate the performance of the 70-gene signature, which result was available for 427 patients (cT1-3N0M0). Adjuvant systemic treatment decisions were based on the Dutch CBO 2004 guidelines, the 70-gene signature and doctors' and patients' preferences. Five-year distant-recurrence-free-interval (DRFI) probabilities were compared between subgroups based on the 70-gene signature and Adjuvant! Online (AOL) (10-year survival probability

Hintergrund: Die histopathologische Diagnostik adulter Granulosazelltumoren (aGCT) beruht auf der Begutachtung morphologischer und immunhistochemischer Kriterien. Aufgrund bislang nicht verfugbarer tumorspezifischer Marker kann die Begutachtung entsprechender Tumoren auch fur den erfahrenen Pathologen in manchen Fallen eine Herausforderung darstellen. Im Jahre 2009 wurde eine fur aGCT spezifische Mutation im FOXL2-Gen beschrieben. Ziel dieser Arbeit war es die Bedeutung der FOXL2-Mutationstestung in einem grosen Kollektiv ursprunglich als aGCT diagnostizierter Tumoren zu untersuchen. Material und Methoden: Etablierung eines Studienkollektives bestehend aus 336 adulten Granulosazelltumoren durch Rekrutierung in drei gynako-onkologischen Zentren (Amsterdam, Helsinki, Tubingen). Samtliche Originaldiagnosen wurden gemas morphologischer und immunhistochemischer Kriterien gestellt. FOXL2-Mutationsanalyse mittels TaqMan Assay, abschliesend spezialisierte Zweitbegutachtung samtlicher FOXL2-negativer Falle. Ergebnisse: Bestatigung der Originaldiagnose „aGCT“ durch Nachweis der FOXL2-Mutation in 76% aller Falle (256/336). In den verbleibenden 24% wurden 63/80 (79%) aller Originaldiagnosen revidiert (Andere Keimstrang-Stromatumore: n = 32; Epitheliale Tumore: n = 29; Andere: n = 2). Bei 72% aller krankheitsbedingten Todesfalle handelt es sich in den ersten 5 Jahren nach Diagnose um Falle mit revidierter Originaldiagnose. Fur das Gesamtuberleben konnte zwischen der Gruppe mit bestatigter Diagnose „aGCT“ (trotz Rezidiven in 28% aller Falle) und einer altersangepassten Kontrollgruppe kein statistisch signifikanter Unterschied gezeigt werden. Diskussion: Samtliche bis zum heutigen Tage verfugbaren Daten und Therapieempfehlungen zur Diagnose „adulter Granulosazelltumor“ beruhen unter Berucksichtigung aktueller Forschungsergebnisse hochstwahrscheinlich auf Studienkollektiven, in denen bis zu 20% falschlicherweise als aGCT diagostizierte Falle enthalten waren. Vor diesem Hintergrund mussen bisherige Erkenntnisse kritisch hinterfragt werden, insbesondere sollte das Potential rein chirurgischer Therapiekonzepte und die auch in der Rezidivsituation gute Prognose der Erkrankung berucksichtigt werden.

The purpose of this study was to study the impact of changes in clinical practice on outcome in patients treated with breast-conserving therapy (BCT) over a period of 28 years. Patients with early invasive breast cancer, who were treated with BCT at the Netherlands Cancer Institute between 1980 and 2008, were studied. Clinical characteristics, treatment and outcome were compared between groups (1980-1987; 1988-1998; 1999-2008). The main endpoint analyzed was ipsilateral breast tumor recurrence (IBTR). 8485 patients with a median follow-up of 9 years (IQR 6-14 years) were analyzed. The cumulative 5- and 10-year IBTR incidences were, respectively, 2 and 5 % for the whole cohort and 4 and 9 % in patients ≤40 years. Young age was a significant risk factor for IBTR in multivariable analysis. IBTR-free interval was better for patients who received a RT boost (HR 0.65) or systemic therapy (HR 0.52). In later years, patients less often received a boost and more often underwent adjuvant systemic treatment. 761 patients (9.0 %) underwent a re-excision; the tumor resection margins were tumor free for 85 %. In later years (1999-2008), 89 % of patients had a tumor-free margin. The margin status of invasive carcinoma did not influence IBTR, DM rate, or OS. Between 1980 and 2008, locoregional control after BCT remained stable with low IBTR rates, even in young patients. These good results were achieved under the policy of accepting close or focally positive margins, indicating this is a safe approach. The results of this study may help in lowering the re-excision rates, which are high in many centers.

The 2012 IMPAKT task force investigated the medical usefulness of current methods for the classification of breast cancer into the 'intrinsic' molecular subtypes (luminal A, luminal B, basal-like and HER2). A panel of breast cancer and/or gene expression profiling experts evaluated the analytical validity, clinical validity and clinical utility of two approaches for molecular subtyping of breast cancer: the prediction analysis of microarray (PAM)50 assay and an immuno-histochemical (IHC) surrogate panel including oestrogen receptor (ER), HER2 and Ki67. The panel found the currently available evidence on the analytical validity and clinical utility of Ki67 based on a 14% cut-off and PAM50 to be inadequate. The majority of the working group members found the available evidence on the analytical validity, clinical validity and clinical utility of ER/HER2 to be convincing. The panel concluded that breast cancer classification into molecular subtypes based on the IHC assessment of ER, HER2 and Ki67 with a 14% cut-off and on the PAM50 test does not provide sufficiently robust information to modify systemic treatment decisions, and recommended the use IHC for ER and HER2 for the identification of clinically relevant subtypes of breast cancers. Methods for breast cancer classification into molecular subtypes should, however, be incorporated into clinical trial design.

Background: Tumors with homologous recombination deficiency (HRD), such as BRCA1-associated breast cancers, are not able to reliably repair DNA double-strand breaks (DSBs) and are therefore highly sensitive to both DSB-inducing chemotherapy and poly (ADP-ribose) polymerase inhibitors. We have studied markers that may indicate the presence of HRD in HER2-negative breast cancers and related them to neoadjuvant chemotherapy response. Patients and methods: Array comparative genomic hybridization (aCGH), BRCA1 promoter methylation, BRCA1 messenger RNA (mRNA) expression and EMSY amplification were assessed in 163 HER2-negative pretreatment biopsies from patients scheduled for neoadjuvant chemotherapy. Results: Features of BRCA1 dysfunction were frequent in triple-negative (TN) tumors: a BRCA1-like aCGH pattern, promoter methylation and reduced mRNA expression were observed in, respectively, 57%, 25% and 36% of the TN tumors. In ER+ tumors, a BRCA2-like aCGH pattern and the amplification of the BRCA2 inhibiting gene EMSY were frequently observed (43% and 13%, respectively) and this BRCA2-like profile was associated with a better response to neoadjuvant chemotherapy. Conclusions: Abnormalities associated with BRCA1 inactivation are present in about half of the TN breast cancers but were not predictive of chemotherapy response. In ER+/HER22 tumors, a BRCA2-like aCGH pattern was predictive of chemotherapy response. These findings should be confirmed in independent series.

Background: Breast cancer cells deficient for BRCA1 are hypersensitive to agents eventually resulting in double-strand DNA breaks, such as platinating agents and poly(ADP-ribose)polymerase (PARP)-inhibitors. Using a BRCA1 array comparative genomic hybridization (aCGH) classifier, we previously identified BRCA1-like tumors with a functional BRCA1-loss, caused by BRCA1-mutation, BRCA1-promoter methylation, or an as yet unidentified mechanism. We observed that these BRCA1- like(CGH) tumors showed an expansive growth pattern, one of the histological features of BRCA1-mutated breast cancer. The aim of this study was to determine which combination of histological features associated with BRCA1-mutated breast cancer were present in the BRCA1-like(CGH) subtype and might predict sensitivity to platinating chemotherapy. Methods: We studied histological features, which are known to be associated with BRCA1-mutations in literature: growth pattern, necrosis, lymphocytic infiltrate and mitotic count. In an independent series of metastatic breast cancer patients (MBC, n=39) for which BRCA1- like(CGH) status was known, whole slides were scored for all features. Features were first tested for significant association with BRCA1- like(CGH) status. Next, significantly associated features were tried in different combinations to find the highest sensitivity to predict for BRCA1- like(CGH) status (BRCA1-histological combination). This histological combination was subsequently tested in stage-III estrogen-receptor low, HER2-negative breast cancer patients, who had been randomized between adjuvant high-dose (HD) platinum-based alkylating chemotherapy and conventional chemotherapy. Additionally, we assessed the association of BRCA1-like(aCGH) status and BRCA1-loss through mutation or promoter methylation with the histological combination in a random subgroup. Results: The combination of a ‘mitotic count above 19 per 2 mm2 with either ‘an expansive growth pattern’ or ‘necrosis’ correctly identified the BRCA1-like(CGH) tumors with a sensitivity of 88% and a specificity of 86% in the MBC patients. In the adjuvant stage-III series, greater benefit was observed from HD-platinum-based chemotherapy versus conventional chemotherapy among patients with the BRCA1-histological combination (41/136=30%, multivariate HR=0.20, 95%CI 0.07-0.62; 7-year recurrence free survival (RFS) 78% versus 39%), compared to patients with other histological features (95/136=70%, HR=0.53, 95%CI 0.29-0.95, 7-year RFS 55% versus 43%), although without a significant difference (test for interaction p=0.14). Analyses of patients with tumors with a mitotic count above 19 only, showed similar results for the BRCA1-histological combination (in this subgroup: expansive growth or necrosis, p-interaction: 0.07). The BRCA1-histological combination was significantly associated with BRCA1-like(CGH) status and BRCA1-mutations, but not with BRCA1-promoter methylation. Conclusion: Using histology only, we were able to identify a large proportion of the aCGH defined BRCA1 molecular subtype. Here, we present the first data that histology might be a biomarker for identifying high-risk patients benefiting from platinum-based chemotherapy in the absence of molecular-based techniques. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr PD01-04.

Introduction Overall survival (OS) of patients with pancreatic ductal adenocarcinoma (PDAC) is extremely poor. Of patients eligible for surgery (20%), around 15% present with a recurrence within 6 months (m), while 10% survive over 5 years after diagnosis. Detailed clinicopathological and molecular knowledge of factors influencing survival may lead to better prognostic and/or predictive factors and preselection of individual patients for specific treatment strategies. Material and methods Fresh frozen PDAC resection specimens from the Academic Medical Centre Amsterdam (1993–2015) were histopathologically revised, and clinicopathological details were collected. From samples with a tumour cellularity of ≥30% (n=90), mRNA, miRNA, and DNA were used for NGS at multiple levels. Corresponding FFPE blocks were selected for tissue microarrays. Results and discussions Unsupervised consensus clustering of gene expression profiles of 90 PDAC revealed four subgroups with divergent OS rates: secretory (14.7 m), epithelial (31.8 m), compound pancreatic (21.5 m), and mesenchymal (14.0 m) subgroups (p=0.002). The differences between the subgroups suggest that more targeted therapy may be feasible for PDAC. The epithelial and mesenchymal subgroups show an upregulation of genes related to DNA repair and hypoxia, respectively, suggesting sensitivity to hyperthermia, which is known to enhance cytotoxic radio-, and chemotherapy effects through frustration of tumour DNA repair and/or better oxygenation of hypoxic tumours. Immune-related gene expression was observed to be upregulated in the compound pancreatic and mesenchymal subtypes; differences were seen in expression of PDL-1, type I interferon, and MHC Class I, which may explain the difference in OS and suggests differential responses to immunotherapeutic agents. Finally, the epithelial subtype is characterised by prominent increases in metabolic signatures. Differences in metabolic flexibility suggest differences in response to mTOR inhibitors. To determine clinical relevance and identify biomarkers, we are currently characterising the subtypes at the miRNA, mutational, copy number, and immunohistochemical level. Conclusion In our well-defined single-centre set of 90 PDAC, we identified four transcriptomics-based subgroups with different survival outcomes that show a correlation with altered DNA-repair-, hypoxia, immune-, and metabolic features. Complete characterisation of these liabilities may help to further identify prognosticators, and preselect patients for specific treatment strategies.

Purpose: Most studies on the sentinel node (SN) procedure in patients with colorectal cancer include immunohistochemical analysis of the SN only. To evaluate the real diagnostic accuracy of the SN procedure with immunohistochemical analysis, the presence of occult tumour cells in all histologically negative lymph nodes was compared to the presence of these cells in SNs. Also the reproducibility of diagnosing occult tumour cells (OTC) and the sensitivity of three different antibodies was assessed. Methods: Between November 2006 en July 2007, an ex vivo SN procedure was performed in 58 histologically NO patients with colorectal cancer. All lymph nodes (n = 908, mean 15.7) were step-sectioned and immunohistochemistry was performed using two antibodies against cytokeratins (Cam5.2, and CK 20) and one antibody against BerEp-4. Results: OTC were identified in 19 of 58 patients, with micrometastases (0.2-2 mm) in 7 and isolated tumour cells (ITC)(

Background The majority of breast cancer patients are postmenopausal women who are increasingly being offered adjuvant chemotherapy. Since the beneficial effect of chemotherapy in postmenopausal patients predominantly occurs in the first 5 years after diagnosis, a prognostic marker for early events can be of use for adjuvant treatment decision making. The aim of this study was to evaluate the prognostic value of the 70-gene prognosis signature for early events in postmenopausal patients. Methods Frozen tumor samples from 148 patients aged 55–70 years were selected (T1–2, N0) and classified by the 70-gene prognosis signature (MammaPrint™) into good or poor prognosis. Eighteen percent received hormonal therapy. Results Breast cancer-specific survival (BCSS) at 5 years was 99% for the good-prognosis signature versus 80% for the poor-prognosis signature group (P = 0.036). The 70-gene prognosis signature was a significant and independent predictor of BCCS during the first 5 years of follow-up with an adjusted hazard ratio of 14.4 (95% confidence interval 1.7–122.2; P = 0.01) at 5 years. Conclusion The 70-gene prognosis signature can accurately select postmenopausal patients at low risk of breast cancer-related death within 5 years of diagnosis and can be of clinical use in selecting postmenopausal women for adjuvant chemotherapy.

Earlier, mapping of the 9p23-24 amplicon in esophageal cancer cell lines led us to the positional cloning of gene amplified in squamous cell carcinoma 1 (GASC1), which encodes a nuclear protein with a Jumonji C domain that catalyzes lysine (K) demethylation of histones. However, the transforming roles of GASC1 in breast cancer remain to be determined. In this study, we identified GASC1 as one of the amplified genes for the 9p23-24 region in breast cancer, particularly in basal-like subtypes. The levels of GASC1 transcript expression were significantly higher in aggressive, basal- like breast cancers compared with nonbasal-like breast cancers. Our in vitro assays demonstrated that GASC1 induces transformed phenotypes, including growth factor-independent proliferation, anchorage-independent growth, altered morphogenesis in Matrigel, and mammosphere forming ability, when overexpressed in immortalized, non-transformed mammary epithelial MCF10A cells. Additionally, GASC1 demethylase activity regulates the expression of genes critical for stem cell self-renewal, including NOTCH1, and may be linked to the stem cell phenotypes in breast cancer. Thus, GASC1 is a driving oncogene in the 9p23-24 amplicon in human breast cancer and targeted inhibition of GASC1 histone demethylase in cancer could provide potential new avenues for therapeutic development. Oncogene (2009) 28, 4491-4500; doi:10.1038/onc.2009.297; published online 28 September 2009

Tumour proliferation is one of the main biological phenotypes limiting cure in oncology. Extensive research is being performed to unravel the key players in this process. To exploit the potential of published gene expression data, creation of a signature for proliferation can provide valuable information on tumour status, prognosis and prediction. This will help individualizing treatment and should result in better tumour control, and more rapid and cost-effective research and development. From in vitro published microarray studies, two proliferation signatures were compiled. The prognostic value of these signatures was tested in five large clinical microarray data sets. More than 1000 patients with breast, renal or lung cancer were included. One of the signatures (110 genes) had significant prognostic value in all data sets. Stratifying patients in groups resulted in a clear difference in survival (P-values

Assessing hormone receptor status is an essential part of the breast cancer diagnosis, as this biomarker greatly predicts response to hormonal treatment strategies. As such, hormone receptor testing laboratories are strongly encouraged to participate in external quality control schemes to achieve optimization of their immunohistochemical assays. Nine Dutch pathology departments provided tissue blocks containing invasive breast cancers which were all previously tested for estrogen receptor and/or progesterone receptor expression during routine practice. From these tissue blocks, tissue microarrays were constructed and tested for hormone receptor expression. When a discordant result was found between the local and TMA result, the original testing slide was revised and staining was repeated on a whole-tissue block. Sensitivity and specificity of individual laboratories for testing estrogen receptor expression were high, with an overall sensitivity of 99.7 and 95.4 %, respectively. Overall sensitivity and specificity of progesterone receptor testing were 94.8 and 92.6 %, respectively. Out of 96 discordant cases, 36 cases would have been concordant if the recommended cut-off value of 1 % instead of 10 % was followed. Overall sensitivity and specificity of estrogen and progesterone receptor testing were high among participating laboratories. Continued enrollment of laboratories into quality control schemes is essential for achieving and maintaining the highest standard of care for breast cancer patients. Electronic supplementary material The online version of this article (doi:10.1007/s10549-015-3444-x) contains supplementary material, which is available to authorized users.

Developing a tissue bank database has become more than just logically arranging data in tables combined with a search engine. Current demand for high quality samples and data, and the ever-changing legal and ethical regulations mean that the application must reflect TuBaFrost rules and protocols for the collection, exchange and use of tissue. To ensure continuation and extension of the TuBaFrost European tissue bank, the custodianship of the samples, and hence the decision over whether to issue samples to requestors, remains with the local collecting centre. The database application described in this article has been developed to facilitate this open structure virtual tissue bank model serving a large group. It encompasses many key tasks, without the requirement for personnel, hence minimising operational costs. The Internet-accessible database application enables search, selection and request submission for requestors, whereas collectors can upload and edit their collection. Communication between requestor and involved collectors is started with automatically generated e-mails.

TuBaFrost is the consortium responsible for the creation of a virtual European human frozen tumour tissue bank: a collection of high quality frozen residual, accurately classified tumour tissue samples, which are stored in European cancer centres and universities. This virtual tissue bank, searchable on the internet, has rules for access and use, and a code of conduct to comply with the various legal and ethical regulations in European countries. The easy accessibility and the European scale of the bank will result in the availability of a large number of samples even of rarer tumour types. Standardisation of collection, storage and quality control throughout the network is achieved minimising inter-institutional variability. A website providing access to upload, search and request samples is a key tool of the tissue bank. The search engine makes use of virtual microscopy. An overview of the development of the European virtual frozen tissue bank infrastructure is described in this paper. The various key aspects are described in more detail in a series of articles to appear in this Journal.

Purpose: The study was designed to determine independent prognostic variables in suboptimally debulked advanced ovarian cancer patients entered in the randomised phase III study EORTC S5865. Experimental design: Retrospectively collected paraffin blocks from 169 patients with stages IIb-IV epithelial ovarian cancer, taken at primary debulking surgery, were analysed. All patients were treated with cyclophosphamide and cisplatin (CP), and followed up for a median of 10 years. Expression of p53, bcl-2, P21, Ki-67 and HER-2 status was assessed by immunohistochemistry (IHC). Results: Expression of p21, a downstream effector of the p53 gene, was found to be a favourable prognostic factor for survival (HR 0.58, Cl 0.36-0.94, p = 0.025) in addition to FIGO stage (HR 1.54, Cl 1.08-2.21, p = < 0.02). For progression free survival (PFS), both p21 (HR 0.52) and Ki-67 (HR 0.6) were significant factors. Conclusion: P21 overexpression is a positive prognostic factor for survival and PFS in advanced ovarian carcinoma with residual lesions of more than 1 cm. (c) 2006 Elsevier Ltd. All rights reserved.

When designing infrastructure for a networked virtual tumour bank (samples remain at the collector institutes and sample data are collected in a searchable central database), it is apparent that this can only function properly after developing an adequate set of rules for use and access. These rules must include sufficient incentives for the tissue sample collectors to remain active within the network and maintain sufficient sample levels in the local bank. These requirements resulted in a key TuBaFrost rule, stating that the custodianship of the samples remains under the authority of the local collector. As a consequence, the samples and the decision to issue the samples to a requestor are not transferred to a large organisation but instead remain with the collector, thus allowing autonomous negotiation between collector and requestor, potential co-authorship in publications or compensation for collection and processing costs. Furthermore, it realises a streamlined cost effective network, ensuring tissue visibility and accessibility thereby improving the availability of large amounts of samples of highly specific or rare tumour types as well as providing contact opportunities for collaboration between scientists with cutting edge technology and tissue collectors. With this general purpose in mind, the rules and responsibilities for collectors, requestors and central office were generated.

Many systems have already been designed and successfully used for sharing histology images over large distances, without transfer of the original glass slides. Rapid evolution was seen when digital images could be transferred over the Internet. Nowadays, sophisticated Virtual Microscope systems can be acquired, with the capability to quickly scan large batches of glass slides at high magnification and compress and store the large images on disc, which subsequently can be consulted through the Internet. The images are stored on an image server, which can give simple, easy to transfer pictures to the user specifying a certain magnification on any position in the scan. This offers new opportunities in histology review, overcoming the necessity of the dynamic telepathology systems to have compatible software systems and microscopes and in addition, an adequate connection of sufficient bandwidth. Consulting the images now only requires an Internet connection and a computer with a high quality monitor. A system of complete pathology review supporting bio-repositories is described, based on the implementation of this technique in the European Human Frozen Tumor Tissue Bank (TuBaFrost).

The RPS6KB1 gene is amplified and overexpressed in approximately 10% of breast carcinomas and has been found associated with poor prognosis. We studied the prognostic significance of P70 S6 kinase protein (PS6K) overexpression in a series of 452 node-negative premenopausal early-stage breast cancer patients (median follow-up: 10.8 years). Immunohistochemistry was used to assess PS6K expression in the primary tumour, which had previously been analysed for a panel of established prognostic factors in breast cancer. In a univariate analysis, PS6K overexpression was associated with worse distant disease-free survival as well as impaired locoregional control (HR 1.80, P 0.025 and HR 2.50, P 0.006, respectively). In a multivariate analysis including other prognostic factors, PS6K overexpression remained an independent predictor for poor locoregional control (RR 2.67, P 0.003). To our knowledge, P70 S6 kinase protein is the first oncogenic marker that has prognostic impact on locoregional control and therefore may have clinical implications in determining the local treatment strategy in early-stage breast cancer patients.

A retrospective study was performed to assess the histopathologic findings in high-risk women undergoing bilateral prophylactic (salpingo)-oophorectomy. The medical files of BRCA1 or BRCA2 mutation carriers and members of a hereditary breast/ovarian cancer (HBOC) family, who had undergone prophylactic surgery, were reviewed. In all, 38 women underwent a bilateral oophorectomy (26 BRCA1, three BRCA2 and nine HBOC, respectively). A total of 90 women underwent bilateral salpingo-oophorectomy (58 BRCA1, six BRCA2, one BRCA1 and 2, 25 HBOC, respectively). At the time of salpingo-oophorectomy, five of 58 BRCA1 carriers (8.6%) were diagnosed with an occult carcinoma: two fallopian tube carcinomas, two ovarian carcinomas and one case was defined as a fallopian tube/ovarian carcinoma. No occult carcinomas were found in the other groups. Of the 38 patients, who underwent a bilateral oophorectomy (mean follow-up 45 months), three of 26 BRCA1 mutation carriers (3.4 in 100 women-years) developed peritoneal papillary serous carcinoma (PPSC) during follow-up. So far, no PPSC have occurred in the 90 women, who underwent a salpingo-oophorectomy (mean follow-up 12 months), including 58 BRCA1 carriers (0 in 60 in women-years). These results contribute to the thesis that BRCA1 germline mutation carriers are not only at risk for ovarian cancer, but also for fallopian tube carcinoma and peritoneal papillary serous carcinoma. Our data suggest that PPSC risk among BRCA2 carriers is lower than among BRCA1 carriers.

We investigated the activity and toxicity of raltitrexed (Tomudex®) as a single agent treatment in patients with Malignant Pleural Mesothelioma (MPM) in a multicentre phase II European Organization for Research and Treatment of Cancer (EORTC) study. This study enrolled chemonaive patients with histologically-confirmed measurable MPM. Raltitrexed was administered at the dose of 3 mg/m2 intravenous (i.v.) bolus on an outpatient basis every 3 weeks. A maximum of eight cycles was planned in cases with an absence of progression or unacceptable toxicity. 24 patients received a total of 104 courses. 5 patients (20.8%, 95% confidence interval (CI) 7.1–42.2%) had a partial response (PR), which was confirmed by an independent radiology committee. Toxicity was mild, with diarrhoea, nausea, vomiting, fatigue and neutropenia as the major side-effects, but not exceeding grade 3 toxicity. We conclude that raltitrexed has activity as a single agent in the treatment of MPM, and that further studies with this drug in MPM are warranted.

Item does not contain fulltext OBJECTIVES: To compare retrospectively the treatment results of surveillance and primary retroperitoneal lymph node dissection (RPLND) of patients with clinical Stage I nonseminomatous germ cell tumors of the testis (NSGCT) in two institutions in The Netherlands. METHODS: From 1982 to 1994, 90 consecutive patients with clinical Stage I NSGCT were prospectively entered in a surveillance protocol in Amsterdam (group 1). In the same period, 101 patients with clinical Stage I NSGCT underwent primary RPLND in Nijmegen (group 2). Both patient populations were comparable for patient age, presence of vascular invasion, and embryonal cell components in the primary tumor. All patients in group 1 with relapse, except for 2, were treated with cisplatin-based chemotherapy. All patients in group 2 with vital tumor in the RPLND specimen were treated with two adjuvant courses of combined chemotherapy (cisplatin, etoposide, and bleomycin). RESULTS: In group 1, at a median follow-up of 7.7 years, 23 patients (26%) had relapse. The median time to relapse was 12 months. Relapses were located retroperitoneally (n = 18, 78%), in the lung (n = 3, 13%), scrotally (n = 1, 4%), and combined in the liver, lung, and pleura (n = 1, 4%). After treatment of relapses (chemotherapy in 21 and/or surgery in 11), only 1 patient died of disseminated disease. A disease-free survival rate of 98.5% was achieved at the median follow-up. The main toxicities consisted of short-lasting leukopenia, accompanied by infection (13%). Four patients reported cardiovascular and four neuropathy complaints. In group 2, the median follow-up was 6.9 years. In 31 patients (30.7%), vital tumor was found retroperitoneally; after two courses of combined chemotherapy, none of them had a relapse. Seven patients with pathologic Stage I disease (6.4%) had a pulmonary relapse within 1 year after surgery. No retroperitoneal relapses were found. After chemotherapy, 6 patients with relapse were salvaged, and 1 died of disseminated disease. The disease-specific survival rate in group 2 was 98% at the median follow-up. The most frequent surgical complications were lymphocele (n = 3), small bowel obstruction (n = 3), and abdominal pain (n = 3). The antegrade ejaculation rate was 94%. CONCLUSIONS: Excellent treatment results in terms of disease-free survival can be achieved in Stage I NSGCT with both surveillance and primary RPLND. Patients with pathologic Stage II disease adjuvantly treated with chemotherapy did not have any relapse and consequently all survived. Most complications after both treatment strategies are reversible. The choice of treatment should be based on balanced information and not on dogmatic principles.

The development of neoplasms is the result of the accumulation of genetic alterations. In breast cancer, large efforts have been dedicated to unravel these genetic alterations and to find associations between specific genetic alterations and the clinical and pathological characteristics of the tumour. There has been rapid advancement of the available techniques to identify new genetic alterations; technical advancement will also place the detection of genetic alterations in breast carcinomas within the grasp of routine clinical testing. As tumour behaviour is largely determined by these genetic alterations, it is to be expected that clinical decision-making in the future will be increasingly influenced by knowledge of the genetic make-up of a tumour. In breast cancer, the main genetic alterations are amplification of approximately 10 oncogenes and inactivation of an unknown number of tumour suppressor genes. In addition, germline mutations in the BRCA1 and 2 genes account for genetic predisposition to develop breast and ovarian cancer. The histological tumour type has been shown to be associated with the presence of specific genetic alterations: for example, inactivation of E-cadherin is specific for the development of lobular breast cancer; HER2 ( c-erb B2) gene amplification is associated with poorly differentiated ductal cancer; and tumours in patients with BRCA1 and 2 germline mutations are often poorly differentiated ductal cancers. Also, associations between specific genetic alterations and clinical behaviour (i.e. metastating potential and sensitivity to systemic treatment) are starting to emerge.

Background and purpose : The aim of this study was to assess the results of treatment (surgery alone or surgery and postoperative radiotherapy) for early-stage cervical carcinoma and to determine the morbidity associated with adjuvant radiotherapy. A subset of these patients ( n =10) was irradiated postoperatively for tumor related negative prognostic factors only and this retrospective analysis was also performed to determine if this decision was right and if the selection for this treatment was based on the right criteria. Material and methods: From 1984 to 1996, 233 women underwent radical hysterectomy as primary treatment of stage I or IIA cervical carcinoma. One hundred and fifty-six patients were treated with surgery alone (67%) and 77 patients (33%) received adjuvant radiotherapy for a, tumor related negative prognostic factors: the combinaton CLS⊕, tumor size ≥40 mm and poor differentiation grade or the combination tumor size ≥40 mm and depth of invasion ≥15 mm ( n =10), or b, positive surgical margins ( n =17), and/or c. lymphnode metastases ( n =42) and/ or d. parametrial involvement ( n =6). Results : For the entire group the most important prognostic factor for survival and disease free survival was node positivity. Additional factors were depth of invasion and positive surgical margins. Thirty-five patients recurred of which 12 after surgery alone. In all these cases the relapse was in the pelvis (100%). Of the 23 recurrences after surgery and adjuvant radiotherapy 13 were seen in the pelvis (56%) ( P =0.003). All patients with negative prognostic factors and N 0, received adjuvant radiotherapy ( n =10) and none of these patients recurred. The incidence of severe gastrointestinal radiation related side effects was low (2%). The incidence of lymphedema of the leg was 11% which was similar in the surgery alone group. Conclusions : The relatively low percentage of radiation related side effects together with 0% recurrence in a subgroup of node negative patients with high risk of recurrence, and a relatively low percentage of recurrence in the surgery alone group lead us to the conclusion that postoperative radiotherapy in special subsets of node negative patients is justified.

Immunostaining revealed the presence of KLK 3, 4, 9 & 11 in all tissue types studied. KLK 5 was present only in KOT’s (p

Bcl-2 has been demonstrated to inhibit apoptosis in breast cancer cells in vitro, and the ratio between Bcl-2 and its proapoptotic homologue Bax seems to be an important determinant of cellular sensitivity to induction of apoptosis. However, little information is available on the relationship between Bcl-2 and the rate of apoptotic and necrotic cell death in breast tumours. From a series of 441 premenopausal, lymphnode-negative breast cancer patients, a subset of 49 tumours was selected in which immunostaining for the 26-kDa isoform of Bcl-2 was either absent (n = 23) or very high (n = 26). High expression of Bcl-2 was found to be strongly associated with low rates of apoptotic (P < 0.001) and necrotic cell death (P < 0.001). The mean value of the apoptotic index was 2.69%+/-1.40% in Bcl-2-negative tumours and 0.68%+/-1.00% in Bcl-2-positive tumours. Expression of the proapoptotic protein Bax correlated neither with Bcl-2 nor with the frequency of apoptotic cells. Immunostaining for the antiapoptotic Bcl-2 homologue BcI-X(L) correlated with Bcl-2 expression (P < 0.001) but not with apoptosis. High proliferation rate and high tumour grade (Bloom-Richardson) were strongly associated with absence of Bcl-2 expression (P< 0.001). p53 accumulation was associated with absence of Bcl-2 expression and increased apoptotic activity. Loss of Bcl-2 expression was strongly correlated with increased apoptotic and necrotic cell death, high proliferation rate and high tumour grade, supporting a model in which Bcl-2 not only mediates cell death, but also cell division in breast cancer tissue, and in which regulation of cell division and cell death are tightly linked. Images Figure 1

Loss of heterozygosity (LOH) frequently occurs in squamous cell carcinomas of the uterine cervix and indicates the probable sites of tumour-suppressor genes that play a role in the development of this tumour. To define the localization of these tumour-suppressor genes, we studied loss of heterozygosity in 64 invasive cervical carcinomas (stage IB and IIA) using the polymerase chain reaction with 24 primers for polymorphic repeats of known chromosomal localization. Chromosomes 3, 11, 13, 16 and 17, in particular, were studied. LOH was frequently found on chromosome 11, in particular at 11q22 (46%) and 11q23.3 (43%). LOH on chromosome 11p was not frequent. On chromosome 17p13.3, a marker (D17S513) distal to p53 showed 38% LOH, whereas p53 itself showed only 20% LOH. On the short arm of chromosome 3, LOH was frequently found (41%) at 3p21.1. The beta-catenin gene is located in this chromosomal region. Therefore, expression of beta-catenin protein was studied in 39 cases using immunohistochemistry. Staining of beta-catenin at the plasma membrane of tumour cells was present in 38 cases and completely absent in only one case. The tumour-suppressor gene on chromosome 3p21.1 may be beta-catenin in this one case, but (an)other tumour-suppressor gene(s) must also be present in this region. For the other chromosomes studied, 13q (BRCA-2) and 16q (E-cadherin), only sporadic losses (< 15% of cases) were found. Expression of E-cadherin was found in all of 37 cases but in six cases the staining was very weak. No correlation was found between clinical and histological parameters and losses on chromosome 3p, 11q and 17p. In addition to LOH, microsatellite instability was found in one tumour for almost all loci and in eight tumours for one to three loci. In conclusion, we have identified three loci with frequent LOH, which may harbour new tumour-suppressor genes, and found microsatellite instability in 14% of cervical carcinomas. Images Figure 1 Figure 4 Figure 5

Aberrant expression of human leukocyte antigens (HLA) class I has prognostic importance in various cancers. Here, we evaluated the prognostic value of classical (A/B/C) and nonclassical (G/E) HLA expression in 169 high grade epithelial ovarian cancer samples and linked that to clinicopathological characteristics and survival. Expression of HLA-A, -B/C, or -E was not correlated with survival. Survival was prolonged when tumours expressed HLA-G(P=0.008)and HLA-G was an independent predictor for better survival(P=0.011). In addition, HLA-G expression was associated with longer progression-free survival(P=0.036)and response to chemotherapy(P=0.014). Accordingly, high expression of HLA-G mRNA was associated with prolonged disease-free survival(P=0.037)in 65 corresponding samples. Elevated serum-soluble HLA-G levels as measured by enzyme-linked immunosorbent assay in 50 matched patients were not correlated to HLA-G protein expression or gene expression nor with survival. During treatment, sHLA-G levels declined(P=0.038). In conclusion, expression of HLA-G is an independent prognostic factor for improved survival in high grade epithelial ovarian cancer and a predictor for platinum sensitivity.

Loss of expression of the intercellular adhesion molecule E-cadherin frequently occurs in invasive lobular breast carcinomas as a result of mutational inactivation. Expression patterns of E-cadherin and the molecules comprising the cytoplasmic complex of adherens junctions, alpha-, beta- and gamma-catenin, were studied in a series of 38 lobular breast carcinomas with known E-cadherin mutation status. The effect of loss of E-cadherin by mutational inactivation (or other mechanisms) on the expression of catenins was investigated. Complete loss of plasma membrane-associated E-cadherin expression was observed in 32 out of 38 invasive lobular carcinomas, for which in 21 cases a mutation was found in the extracellular domain of E-cadherin. In total, 15 frameshift mutations of small deletions or insertions, ranging from 1 to 41 bp, three non-sense mutations, and three splice mutations were identified. Mutations were scattered over the whole coding region and no hot spots could be detected. In all cases, simultaneous loss of E-cadherin and alpha- and beta-catenin expression was found; in 50 per cent of these cases, additional loss of gamma-catenin was observed. In six invasive lobular carcinomas, expression of both E-cadherin and catenins was retained. In none of these carcinomas was an E-cadherin mutation detected. Lobular carcinoma in situ adjacent to invasive lobular carcinoma showed simultaneous loss of E-cadherin and catenins in all the cases studied--remarkably, also, in four cases positive for E-cadherin and catenin expression in the invasive component. These results indicate that simultaneous loss of E-cadherin and alpha-, beta- and gamma-catenin may be an important step in the formation of lobular carcinoma in situ, as a precursor of invasive lobular breast cancer. Events additional to E-cadherin inactivation must be involved in the transition of lobular carcinoma in situ to invasive lobular carcinoma

Clinical guidelines for breast cancer treatment differ in their selection of patients at a high risk of recurrence who are eligible to receive adjuvant systemic treatment (AST). The 70-gene signature is a molecular tool to better guide AST decisions. The aim of this study was to evaluate whether adding the 70-gene signature to clinical risk prediction algorithms can optimize outcome prediction and consequently treatment decisions in early stage, node-negative breast cancer patients. A 70-gene signature was available for 427 patients participating in the RASTER study (cT1-3N0M0). Median follow-up was 61.6 months. Based on 5-year distant-recurrence free interval (DRFI) probabilities survival areas under the curve (AUC) were calculated and compared for risk estimations based on the six clinical risk prediction algorithms: Adjuvant! Online (AOL), Nottingham Prognostic Index (NPI), St. Gallen (2003), the Dutch National guidelines (CBO 2004 and NABON 2012), and PREDICT plus. Also, survival AUC were calculated after adding the 70-gene signature to these clinical risk estimations. Systemically untreated patients with a high clinical risk estimation but a low risk 70-gene signature had an excellent 5-year DRFI varying between 97.1 and 100 %, depending on the clinical risk prediction algorithms used in the comparison. The best risk estimation was obtained in this cohort by adding the 70-gene signature to CBO 2012 (AUC: 0.644) and PREDICT (AUC: 0.662). Clinical risk estimations by all clinical algorithms improved by adding the 70-gene signature. Patients with a low risk 70-gene signature have an excellent survival, independent of their clinical risk estimation. Adding the 70-gene signature to clinical risk prediction algorithms improves risk estimations and therefore might improve the identification of early stage node-negative breast cancer patients for whom AST has limited value. In this cohort, the PREDICT plus tool in combination with the 70-gene signature provided the best risk prediction. Electronic supplementary material The online version of this article (doi:10.1007/s10549-014-2954-2) contains supplementary material, which is available to authorized users.

Purpose: The Imagio® breast imaging system, a diagnostic opto-acoustic (OA) imaging device bearing the CE Mark, is in the U.S. FDA Premarket Approval process. OA provides both functional (relative oxygenation/de-oxygenation) and anatomic (angiogenesis) information that is co-registered and temporally interleaved in real time with gray-scale ultrasound that may improve distinction between benign and malignant masses. OA imaging pathology correlation was performed to elucidate the histologic features of OA features of breast cancers. Methods and Materials: A multicenter postmarket surveillance and clinical follow-up study was conducted in five Dutch sites in which 209 women with breast masses underwent OA prior to biopsy. Histopathology examination of the biopsies revealed 146 benign masses (mostly fibroadenomas) and 76 malignant masses (mostly invasive ductal carcinomas). For invasive ductal carcinomas, histologic grade and the features used to assess histologic grade (nuclear pleomorphism, tubule formation, and mitotic count) were assessed. For each mass, 5 pre-determined OA features, 3 internal features, and 2 external features were evaluated. The 3 internal scores (vessels, blush, and hemoglobin) and 2 external features (capsular boundary zone and peripheral boundary zone) were separately and collectively summed for testing relationships with traditional histopathology measures using a two-sided Jonckheere-Terpstra test of ordered outcomes. Distribution differences between benign and malignant masses were performed using a Wilcoxon Rank Sum test for each internal, external, and summed total internal, external, and total score. Results: The mean differences were significantly higher for malignant vs. benign for internal vessels (p=0.0009), internal blush (p=0.0085), external boundary zone (p Conclusion: OA feature summary scores appear to differentiate between benign vs. malignant and correspond to histologic grade and scoring components of histologic grade. The U.S. investigational PIONEER pivotal study (n=2,095) may further confirm these results. Citation Format: van de Vijver M, Lavin PT, Stavros AT. Breast biopsy histology relationships with opto-acoustic imaging of breast masses [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-02-03.

Om te begrijpen wat kanker is en wat de impact ervan kan zijn, is het belangrijk om kennis te hebben van het ontstaan van kanker en de mogelijkheden betreffende de diagnostiek en stadiering van kanker.