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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 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

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.

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.

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.

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)(

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.

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.

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.

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.

Locoregional recurrence (LRR) after breast-conserving therapy is a well-known independent risk factor associated with unfavourable long-term outcome. Controversy exists concerning the prognostic impact of a LRR after a very long event-free interval. Patients who underwent breast-conserving therapy for early stage breast cancer were pooled from four European Organisation for Research and Treatment of Cancer (EORTC) Breast Group trials. Only LRR as a first event was taken into account. Risk factors such as tumour size, nodal status, young age and chemotherapy were assessed in multivariate Cox regression analysis. LRR was used as a time-dependent variable in the landmark analysis for distant disease-free survival (DFS) and overall survival (OS). Patients were categorised as having at least 0, 5 or 10 years event-free survival. In total, 7751 early stage breast cancer patients were included with a median follow-up of 10.9 years. Tumour size, nodal status, young age and chemotherapy are strong independent prognostic factors with a significant impact on long-term outcome, but lose their power and significance over time. Including all patients, LRR was the strongest prognostic factor for OS and distant DFS (resp. HR 5.01 and HR 5.31, p

Background: Breast cancer cells deficient for BRCA1 are hypersensitive to agents inducing DNA double-strand breaks (DSB), such as bifunctional alkylators and platinum agents. Earlier, we had developed a comparative genomic hybridisation (CGH) classifier based on BRCA1-mutated breast cancers. We hypothesised that this BRCA1-likeCGH classifier could also detect loss of function of BRCA1 due to other causes besides mutations and, consequently, might predict sensitivity to DSB-inducing agents. Patients and methods: We evaluated this classifier in stage III breast cancer patients, who had been randomly assigned between adjuvant high-dose platinum-based (HD-PB) chemotherapy, a DSB-inducing regimen, and conventional anthracycline-based chemotherapy. Additionally, we assessed BRCA1 loss through mutation or promoter methylation and immunohistochemical basal-like status in the triple-negative subgroup (TN subgroup). Results: We observed greater benefit from HD-PB chemotherapy versus conventional chemotherapy among patients with BRCA1-likeCGH tumours [41/230 = 18%, multivariate hazard ratio (HR) = 0.12, 95% confidence interval (CI) 0.04–0.43] compared with patients with non-BRCA1-likeCGH tumours (189/230 = 82%, HR = 0.78, 95% CI 0.50–1.20), with a significant difference (test for interaction P = 0.006). Similar results were obtained for overall survival (P interaction = 0.04) and when analyses were restricted to the TN subgroup. Sixty-three percent (20/32) of assessable BRCA1-likeCGH tumours harboured either a BRCA1 mutation (n = 8) or BRCA1 methylation (n = 12). Conclusion: BRCA1 loss as assessed by CGH analysis can identify patients with substantially improved outcome after adjuvant DSB-inducing chemotherapy when compared with standard anthracycline-based chemotherapy in our series.

Background The response of primary breast cancer to chemotherapy is usually expressed either as a pathological complete remission (pCR) or as ‘no pCR’. A more quantitative measure is called for. Patients and methods The ‘neoadjuvant response index’ (NRI) was calculated by adding a breast response score (a number from a five-point scale) to an axillary response score (a number from a three-point scale) and dividing this by the score that would have been obtained in case of a pCR in both breast and axilla. Consequently, the NRI is a number between 0 (representing no response) and 1 (a pCR of both breast and axilla). Results The NRI was calculated in 267 patients who had received neoadjuvant chemotherapy. The average NRI was 0.48 (median 0.40). Forty-one patients (15%) had an NRI of 0; 55 patients (21%) had an NRI of 1 (pCR). ‘Highly endocrine responsive’ tumors responded substantially less than ‘incompletely endocrine responsive’ ones. In triple negatives, an NRI of >0.70 was associated with a better recurrence-free survival than a lower NRI. Conclusions The NRI proposed here may be useful to better reflect the efficacy of neoadjuvant systemic regimens than the binary pCR–‘no pCR’ system.

Background: It is well known that there is considerable inter-observer variability in assessment of the pathological parameters that are used to select node-negative breast cancer patients for adjuvant systemic treatment. There are only limited data available as to in how many patients this leads to differences in treatment decisions. Methods: Clinical and pathological data of 694 patients

High-throughput genetic analysis of breast cancer results in improved classification of breast cancer and can be used to identify prognostic and predictive factors. These prognostic and predictive factors are increasingly useful to guide therapy decisions in individual breast cancer patients. There is a rapidly increasing body of literature on gene expression signatures associated with prognosis; and on gene expression signatures associated with response to specific systemic treatment, including chemotherapy, hormonal therapy and HER2 targeted therapy. The main prognostic profiles published to date are a 70-gene signature identified by our group in the Netherlands Cancer Institute (Amsterdam, the Netherlands); a 76-gene prognosis profile identified by investigators from Erasmus Medical Centre (Rotterdam, the Netherlands; a 21-gene recurrence score developed by the company Genomic Health (Redwood City, USA); and a genomic-grade signature developed by investigators at the Institut Bordet (Brussels, Belgium). Breast cancer is a very heterogeneous disease, and prognostic and predictive profiles may differ in breast cancer subtypes. We are therefore currently performing gene expression profiling studies, assessment of DNA copy number changes and miRNA expression profiles in triple-negative breast cancers (n = 96) and HER2-positive breast cancers (n = 140). Prognostic classifiers can be used to identify patients that will benefit most from adjuvant systemic therapy, but other classifiers will be needed to decide which treatment should be given. To guide the choice of chemotherapy, hormonal therapy and targeted therapy, neoadjuvant studies are well suited to identify predictive factors for therapy response. For this purpose, we have analysed gene expression profiles in pretreatment biopsies of 191 patients treated with neoadjuvant chemotherapy; and patients with HER2-positive breast cancer treated with the combination of chemotherapy and trastuzumab. Our results and studies from various other groups show that basal-type/triple-negative tumors show a pathological complete remission in 30 to 40% of cases; as compared with

Pathologie is een klinisch diagnostisch vak, waarbij met de hulp van de microscoop onderzoek wordt gedaan van biopten, opgezogen cellen of bij operatie verwijderd weefsel. De op deze wijze gestelde diagnose geeft in belangrijke mate richting aan de behandeling van de patient. Vooral door de sterk toegenomen kennis van ziekteprocessen op moleculair niveau is het voor de patholoog mogelijk om steeds nauwkeuriger een diagnose te stellen, waardoor de behandeling steeds beter op de individuele patient gericht kan worden. De pathologie speelt een centrale rol bij het snel in omvang toenemende translationele onderzoek. Er moet voor gezorgd worden dat geneeskundestudenten een gedegen inzicht hebben in de mogelijkheden van pathologisch onderzoek; en dat er een groter aantal medisch specialisten wordt opgeleid met kennis van translationeel onderzoek. Dit zal er toe bijdragen dat bevindingen uit het basale onderzoek sneller en beter hun weg naar de kliniek vinden.

Most invasive breast cancers are classified as invasive ductal carcinoma not otherwise specified (IDC NOS), whereas about 25% are defined as histological 'special types'. These special-type breast cancers are categorized into at least 17 discrete pathological entities; however, whether these also constitute discrete molecular entities remains to be determined. Current therapy decision-making is increasingly governed by the molecular classification of breast cancer (luminal, basal-like, HER2+). The molecular classification is derived from mainly IDC NOS and it is unknown whether this classification applies to all histological subtypes. We aimed to refine the breast cancer classification systems by analysing a series of 11 histological special types [invasive lobular carcinoma (ILC), tubular, mucinous A, mucinous B, neuroendocrine, apocrine, IDC with osteoclastic giant cells, micropapillary, adenoid cystic, metaplastic, and medullary carcinoma] using immunohistochemistry and genome-wide gene expression profiling. Hierarchical clustering analysis confirmed that some histological special types constitute discrete entities, such as micropapillary carcinoma, but also revealed that others, including tubular and lobular carcinoma, are very similar at the transcriptome level. When classified by expression profiling, IDC NOS and ILC contain all molecular breast cancer types (ie luminal, basal-like, HER2+), whereas histological special-type cancers, apart from apocrine carcinoma, are homogeneous and only belong to one molecular subtype. Our analysis also revealed that some special types associated with a good prognosis, such as medullary and adenoid cystic carcinomas, display a poor prognosis basal-like transcriptome, providing strong circumstantial evidence that basal-like cancers constitute a heterogeneous group. Taken together, our results imply that the correct classification of breast cancers of special histological type will allow a more accurate prognostication of breast cancer patients and facilitate the identification of optimal therapeutic strategies.

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 and specificity [corrected] 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.

The regulatory regimes for research with residual tissue and accompanying data differ widely between countries in the European Union (EU): from specific consent to opt-out or even no consent at all. This could greatly hamper research where the exchange of tissue and accompanying data has become the gold standard, like in TubaFrost. Instead of adhering to international guidelines, which have a democratic deficit, or an attempt for a new set of possible harmonising rules, TubaFrost chose to create a coordinating rule: if tissue may legitimately be used for a certain kind of research in the country where it was taken and under whose jurisdiction the patient falls, it may also be used for such research in the country where it is sent to in the context of a scientific program even if in that other country other regulations would apply for research with residual tissue taken from patients under their jurisdiction. This coordinating rule has a sound basis in EU law in general and will solve the problems related to diverging national regulatory regimes in the case of cross national research with residual tissue.

Tumour Bank Networking presents a great challenge for oncological research as in order to carry out large-scale, multi-centre studies with minimal intrinsic bias, each tumour bank in the network must have some fundamental similarities and be using the same standardised and validated procedures. The European Human Frozen Tumour Tissue Bank (TuBaFrost) has responded to this need by the promotion of an integrated platform of tumour banks in Europe. The operational framework for TuBaFrost has drawn upon the best practice of standard workflows and operating procedures employed by members of the TuBaFrost project and key initiatives worldwide.

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).

TuBaFrost is a consortium responsible for the task to create a virtual European human frozen tumor tissue bank, composed of high quality frozen tumor tissue collections with corresponding accurate diagnosis stored in European cancer centers and universities, searchable on the Internet, providing rules for access and use and a code of conduct to comply with the various legal and ethical regulations in European countries. Such infrastructure would enlarge tissue availability and accessibility in large amounts of specified or even rare tumor samples. Design of an infrastructure for European residual tissue banking with the described characteristics, clear focus points emerge that can be broken down in dedicated subjects: (1) standardization and quality assurance (QA) to avoid inter-institute quality variation; (2) law and ethics enabling exchange of tissue samples possible between institutes in the different European countries, where law and ethics are characterized by a strong variability; (3) rules for access, with sufficient incentives for collectors; (4) central database application containing innovations on search and selection procedures; (5) support when needed with histology images; and (6) Internet access to search and upload, with in addition a solid website giving proper information on the procedures, intentions and activities not only to the scientific community, but also to the general public. One consortium decision, part of the incentives for collectors, had major impact on the infrastructure; custodianship over the tissues as well as the tissues stay with the collector institute. Resulting in specimens that are not given to an organization, taking decisions on participation of requests, but instead the local collected tissues stay very easy to access by the collector and allows autonomous negotiation between collector and requestor on cooperation, coauthorship in publication or compensation in costs. Thereby, improving availability of large amounts of high quality samples of a highly specified or rare tumor types and contact opportunities for cooperation with other institutes.

Prognostic and predictive factors play important roles in the treatment of breast cancer. Genome-wide monitoring of gene expression using DNA microarrays makes it possible to study thousands of genes in a tumour sample in a single experiment. By looking for an association between the gene expression pattern and tumour behaviour, it should be possible to identify new prognostic and predictive factors.

The role of high-dose chemotherapy in the adjuvant treatment of high-dose breast cancer has not been established. Results have been reported from six randomized studies with a symmetrical study design (Table ​(Table1).1). All show a lower relapse rate in the high-dose arm, but in only one study was this result statistically significant. Table 1 Randomized studies evaluating the role of high-dose chemotherapy in high-risk breast cancer Methods Patients below 56 years of age who had undergone surgery for stage II or III breast cancer were eligible if they had at least four tumor-positive axillary lymph nodes. Patients in the conventional dose (CD) arm received five courses of FEC (fluorouracil 500 mg/m2, epirubicin 90 mg/m2 and cyclophosphamide 500 mg/m2; every 3 weeks) followed by radiation therapy and tamoxifen. The high-dose (HD) arm was identical, except that high-dose chemotherapy (CTC [cyclophosphamide 6 g/m2, thiotepa 480 mg/m2 and carboplatin 1600 mg/m2]) with peripheral blood progenitor cell reinfusion was given instead of the fifth FEC course.

This study assesses the potential value of the tumor markers p53, HER2, and Bcl-2 in predicting the clinical response to doxorubicin and paclitaxel as single agents in the treatment of metastatic breast cancer. The primary tumors of 114 patients in the European Organization for Research and Treatment of Cancer 10923 trial were assessed by immunohistochemistry using monoclonal antibodies; the results were correlated with clinical response to therapy. HER2 was positive in 24% of patients, p53 was positive in 25% of patients, and Bcl-2 was positive in 49% of patients. There was no correlation between the expression of any of the markers and the clinical response to either agent. Although methodologically limited, this study does not support the use of p53, HER2, or Bcl-2 to assist the selection of anthracycline versus taxane in metastatic breast cancer.

PURPOSE: In view of the increasing number of patients treated with breast-conserving treatment (BCT) for ductal carcinoma-in-situ (DCIS), risk factors for recurrence and metastasis should be identified. PATIENTS AND METHODS: Clinical and pathologic characteristics from patients with DCIS in the European Organization for Research and Treatment of Cancer trial 10853 (excision with or without radiotherapy) were related to the risk of recurrence. Pathologic features were derived from a central review of 863 of the 1,010 randomized cases (85%). The median follow-up was 5.4 years. RESULTS: Factors associated with an increased risk of local recurrence in the multivariate analysis were young age (≤ 40 years) (hazard ratio, 2.14; P = .02), symptomatic detection of DCIS (hazard ratio, 1.80; P = .008), growth pattern (solid and cribriform) (hazard ratios, 2.67 and 2.69, respectively; P = .012), involved margins (hazard ratio, 2.07; P = .0008), and treatment by local excision alone (hazard ratio, 1.74; P = .009). The risk of invasive recurrence was not related to the histologic type of DCIS (P = .63), but the risk of distant metastasis was significantly higher in poorly differentiated DCIS compared with well-differentiated DCIS (hazard ratio, 6.57; P = .01). CONCLUSION: Patients with poorly differentiated DCIS have a high risk of distant metastasis after invasive local recurrence. Margin status is the most important factor in the success of BCT for DCIS; additionally, young age and symptomatic detection of DCIS have negative prognostic value.