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The aim of this study was to see how effective ultrasound-guided needle biopsy was at detecting lymph node involvement in patients with early breast cancer. Patients with newly diagnosed invasive breast cancer underwent axillary ultrasound (US) where lymph node size and morphology were noted. A core biopsy (CB) was undertaken of any node greater than 5 mm in longitudinal section. Patients with benign CBs proceeded to sentinel lymph node (SLN) biopsy, whereas those with malignancy underwent axillary lymph node dissection (ALND). US and CB findings were correlated with final surgical histology in all cases. One hundred and thirty-nine patients were examined, of whom 52.5% had lymph node metastases on final histology. One hundred and twenty-one patients (87%) underwent axillary node CB. The overall sensitivity of CB for detecting lymph node metastases was 53.4% (60.3% for macrometastases; 26.7% for micrometastases). The US morphological characteristics most strongly associated with malignancy were absence of a hilum and a cortical thickness greater than 4 mm. However, one third of patients with normal lymph node morphology had nodal metastases, and only 12% of these were diagnosed on CB. CB of axillary lymph nodes can diagnose a substantial number of patients with lymph node metastases, allowing these patients to proceed directly to ALND, avoiding unnecessary SLN biopsy.

Inactivation of the transcription factor p53 is central to carcinogenesis. Yet only approximately one-half of cancers have p53 loss-of-function mutations. Here, we demonstrate a mechanism for p53 inactivation by apoptosis repressor with caspase recruitment domain (ARC), a protein induced in multiple cancer cells. The direct binding in the nucleus of ARC to the p53 tetramerization domain inhibits p53 tetramerization. This exposes a nuclear export signal in p53, triggering Crm1-dependent relocation of p53 to the cytoplasm. Knockdown of endogenous ARC in breast cancer cells results in spontaneous tetramerization of endogenous p53, accumulation of p53 in the nucleus, and activation of endogenous p53 target genes. In primary human breast cancers with nuclear ARC, p53 is almost always WT. Conversely, nearly all breast cancers with mutant p53 lack nuclear ARC. We conclude that nuclear ARC is induced in cancer cells and negatively regulates p53.

Using a portable terahertz pulsed spectrometer developed by TeraView Ltd. the complex refractive indices of ex vivo breast tumors were measured through transmission in the range of 0.1-3 THz. Twenty samples were measured at room temperature and it is shown here that the use of terahertz pulsed spectroscopy (TPS) enables us to distinguish between normal adipose tissue, normal fibrous tissue and breast tumors due to the higher water content and structural differences found in tumors. Comparisons are made between the results found using TPS and the classification of the tissue samples given through histology performed at Addenbrooke's Hospital, Cambridge. Further measurements have been taken at low temperatures (down to 200 K) to remove the dominant absorption caused by water in an attempt to identify other differences, such as the cell and protein density, between normal breast tissue and tumors observable in the THz range.

Histopathologists are encountering intra-lobular epithelial proliferations more frequently in core biopsies taken from lesions identified in mammographic breast screening programmes. In particular, columnar cell lesions are increasingly being seen in core biopsies taken for the histological assessment of mammographically detected microcalcifications. The morphological features of lobular neoplasia are relatively well known, but columnar cell lesions, particularly forms with atypical features, are less widely recognised. The biological and clinical significance of both of these intra-lobular processes is controversial, (1) as indicators of adjacent malignancy when encountered in core biopsy, (2) the relative risk conferred of development of subsequent malignancy, and (3) their precursor behaviour. For this reason, the optimal clinical management of these lesions, particularly when encountered on core biopsy, is unclear. This review provides an update on the histological diagnosis of lobular neoplasia and columnar cell lesions and outlines recent clinico-pathological and molecular findings with discussion on clinical management.

Neoadjuvant chemotherapy is increasingly being offered to patients with invasive breast carcinoma but surgical excision specimens following such therapy may be difficult to interpret in the pathology laboratory, both macroscopically and histologically. We provide here some guidelines for handling such postneoadjuvant chemotherapy samples and describe the histopathological features which may be encountered in both the breast and lymph nodes received. We also present a brief review of the literature and suggest a simple method for quantifying the degree of response to neoadjuvant chemotherapy in both the primary breast carcinoma and the lymph nodes.

summary Considerable heterogeneity of morphology and disease outcome exists within breast cancers (BC), which likely reflects variable molecular pathogeneses within this broad clinical group. Aim To evaluate the underlying genomic alterations associated with familial, early-onset BC (EOBC) phenotypes, in order to improve the management of this disease. Methods Using hierarchical clustering of morphological and immunophenotypical parameters, 116 EOBC were stratified into six groups. Conventional and array-based comparative genomic hybridisation was used to analyse the genomic alterations. Results Specific areas of genomic imbalance were associated with individual phenotypes. The largest phenotypical group was high grade, oestrogen receptor and HER-2 negative. This group contained the majority of BRCA1 germline mutation-associated tumours and commonly showed loss of chromosomal regions 5cent-5q13, 5q14–22 and 4q28-32. High mitotic rate, an important indicator of tumour cell proliferation and poor prognosis, was associated with gain of 19p, mapped within 7 Mb of the telomere. This region contains the candidate oncogene CDC34, the protein product of which is involved in ubiquitin-mediated degradation of the cyclin-dependent kinase inhibitor, p27 Kip1 . Conclusion Phenotype-based analysis can be used to determine the genetic changes important in subtypes of BC. Further, the different morphological phenotypes could act as a cost-effective surrogate for genotypical stratification to facilitate optimal management of this disease.

Human mRNA DeXD/H-box helicases are ubiquitous molecular motors that are required for the majority of cellular processes that involve RNA metabolism. One of the most abundant is eIF4A, which is required during the initiation phase of protein synthesis to unwind regions of highly structured mRNA that would otherwise impede the scanning ribosome. Dysregulation of protein synthesis is associated with tumorigenesis, but little is known about the detailed relationships between RNA helicase function and the malignant phenotype in solid malignancies. Therefore, immunohistochemical analysis was performed on over 3000 breast tumors to investigate the relationship among expression of eIF4A1, the helicase-modulating proteins eIF4B, eIF4E and PDCD4, and clinical outcome. We found eIF4A1, eIF4B and eIF4E to be independent predictors of poor outcome in ER-negative disease, while in contrast, the eIF4A1 inhibitor PDCD4 was related to improved outcome in ER-positive breast cancer. Consistent with these data, modulation of eIF4A1, eIF4B and PCDC4 expression in cultured MCF7 cells all restricted breast cancer cell growth and cycling. The eIF4A1-dependent translatome of MCF7 cells was defined by polysome profiling, and was shown to be highly enriched for several classes of oncogenic genes, including G-protein constituents, cyclins and protein kinases, and for mRNAs with G/C-rich 5′UTRs with potential to form G-quadruplexes and with 3′UTRs containing microRNA target sites. Overall, our data show that dysregulation of mRNA unwinding contributes to the malignant phenotype in breast cancer via preferential translation of a class of genes involved in pro-oncogenic signaling at numerous levels. Furthermore, immunohistochemical tests are promising biomarkers for tumors sensitive to anti-helicase therapies.

We have developed a portable terahertz pulsed imaging system (TPI Imaga1000) for use in a clinical environment. The system uses photoconduction to generate and detect terahertz radiation with frequency content from 0.1-4 THz. Here, we report on a study using TPI for imaging breast tumours ex vivo. Several breast samples were imaged and parameters from the time domain impulse functions were used to provide contrast. The size and shape of tumour regions in the terahertz images were compared with the corresponding histology section. Good correlation was found for area and shape of tumour in the THz images compared to that of histology. In addition, we have also performed spectroscopy study comparing the terahertz properties (absorption coefficient and refractive index) of excised normal breast skin and breast tumor. Both the absorption coefficient and refractive index were higher for tissue containing tumor compared to normal. These changes are consistent with higher water content and structural changes, like increased cell and protein density. This study demonstrates the potential of TPI to image both invasive breast carcinomas and ductal carcinoma in situ using THz and encourages further studies.

Ductal carcinoma in situ represents about 20% of all tumours diagnosed within mammographic screening programs. The natural history of DCIS is poorly understood, as it cannot be observed directly. Estimates of the proportion of DCIS that progress to invasive cancer, as well as factors that may influence progression, are important for clinical management. Here we review various sources of evidence regarding the natural history of DCIS. We identified relevant publications of studies on: follow-up studies of DCIS initially misdiagnosed as benign, studies of recurrence of DCIS as invasive cancer, autopsy studies, studies of risk factors for DCIS, animal studies and studies that used mathematical models to study growth of DCIS and invasive cancer. Data sources included the MEDLINE data base, searches of articles cited in key reviews and editorials. The most direct evidence regarding the progression of DCIS to invasive cancer comes from studies where DCIS was initially misdiagnosed as benign and treated by biopsy alone. These studies suggest that between 14–53% of DCIS may progress to invasive cancer over a period of 10 or more years. The reported prevalence of undiagnosed DCIS in autopsy studies, of approximately 9%, has been used to suggest a larger reservoir of DCIS may exist in the population. All types of study designs reviewed had limitations that may bias the estimate of progression in either direction. The available evidence suggests not all DCIS will progress to invasive cancer in the medium term but precise estimates of progression are not possible given the limitations of the data. Mathematical modelling of various scenarios of progression and studies of genetic factors involved in progression may shed further light on the natural history of DCIS.

1014 Background: Bevacizumab (bev) has been used with NACT in breast cancer trials. Geparquinto reported benefit for bev in triple negative (neg) patients (pts) (pCR 36.4% v 27.8% p=0.02), as did C...

S S37 operation while 7 patients (7/43) that had negative cytology at FNAC had positive lymph nodes identified at SLNB and therefore required a second surgical procedure (ANC). Conclusion: WBN has been found to be a superior interventional technique when interrogating the axilla. We therefore recommend that wide bore core biopsy should be adopted routinely in preoperative axillary staging. It reduces the need for second procedure, improves patient pathway and be cost beneficial to the health care. http://dx.doi.org/10.1016/j.ejso.2015.03.072 P035. Reaching a national consensus on the surgical management of multiple ipsilateral breast cancers (MIBCs): Perceptions by patients, healthy volunteers, surgeons and breast cancer associations Zoe Winters, Ramsey Cutress, Rosemary Greenwood, Jenny Ingram, on behalf of the CONSERVE Trial TMG 1 University of Bristol, Bristol, UK University of Southampton, Southampton, UK Research Design Support University Hospitals of Bristol NHS Foundation Trust, Bristol, UK Aims: To develop a pragmatic randomized trial evaluating the clinical safety of breast conserving surgery (BCS) versus the standard of mastectomy in treating all types of MIBCs (multifocal and multicentric), it was important to assess the perceptions of patients and public on the current evidence and rationale for a new trial. Methods: A Bristol Online Survey (October-November 2013) was designed by the Trial Management Group (TMG) including questions on: use of MRI, perceptions of biological differences between unifocal and MIBCs, and surgical recommendations for the treatment of multifocal (MF: foci in same quadrant) and multicentric (MC: foci in separate quadrants) cancers. Four separate focus groups (n1⁄4 30) where scheduled involving breast cancer patients, healthy volunteers and patient advocacy groups. Results: 176 surgeons (46%) responded. 19% of surgeons regard the current clinical evidence as ‘sufficient’, compared to 40% who disagree and 41% who are ‘unsure’. Surgeons thought that MIBCs should be treated ‘differently’ (45%) from unifocal cancers or they expressed ‘uncertainty’ (47%). The overwhelming majority (85%) indicated that they would treat MIBCs by Mastectomy. A minority of surgeons recommended BCS in 22% of MF cancers, compared to 8% of MC cancers. 67% per cent of surgeons thought that a trial addressing the clinical safety of oncoplastic BCS was an important clinical question. PPI groups strongly supported the chance for BCS providing they could be reassured of safety measures within a trial. They wanted full information of all potential trial benefits. Conclusions: There is a strong case for a feasibility trial supported by national perceptions. Surgeons are more ‘uncertain’ about the treatment of MF compared to MC cancers. http://dx.doi.org/10.1016/j.ejso.2015.03.073 P036. Audit of breast local recurrence rates in a District General Hospital Marianne Rice, Justin Ong, J. McGregor, Helen Mathers Craigavon Area Hospital, N. Ireland, UK Introduction: The aim of breast cancer surgery is to achieve good local control of the primary tumour and regional nodes. The START trial showed excellent rates of local recurrence following breast conservation in the UK. Revised Association of Breast Surgery (ABS) Guidelines recommend minimum local recurrence rates of

1015 Background: Neo-tAnGo was an NCRI UK neoadjuvant breast cancer study testing the addition of gemcitabine to anthracycline and taxane-based treatment and also the sequencing of chemotherapy. In a translational substudy, sequential fresh tissue was analysed for PAM 50 subgroups. Methods: Neo-tAnGo recruited 831 patients. 162 patients were consented for Neo-tAnGo Science, for 3 additional fresh tissue samples to be taken at diagnosis (diag), mid-chemotherapy (CT) and end-CT. Standard methodology was used for PAM 50 subtyping. Results: Fresh tissue samples at diag were received from 123 patients (pts). 45 pts (37%) had 2 additional samples provided (at mid- and end-CT). 57 pts (46%) had 1 additional sample provided (34 at mid-CT, 23 at end-CT). PAM 50 subtyping at diag was as follows: 31 (25%) BASAL; 30 (24%) HER2; 39 (32%) LUM B; 13 (11%) LUM A; 10 (8%) NORMAL-like. Pathological complete response rates (pCR: no disease in breast or axillary nodes, n = 121 pts) differed between PAM 50 subtype at diag (p = 0.04): BASAL 11/31 (35%); HER2 8/30 (27%); LUM B 3/37 (8%); LUM A 1/13 (8%); NORMAL-like 3/10 (30%). Of the 94 pts who were not PAM50 NORMAL-like at diag and had 2+ samples, 42 (45%) ‘shifted to NORMAL-like’. This was associated with slightly higher pCR rates (24% vs 15% who didn’t ‘shift to NORMAL-like’, p = 0.44) and borderline significantly higher rates of pCR or minimal residual disease (MRD

Introduction Population-based studies of breast cancer have estimated that some PALB2 mutations confer a breast cancer risk (penetrance) comparable to the average pathogenic mutation in BRCA2. As this risk is of clinical relevance, we sought to identify mono-allelic PALB2 mutations and determine their frequencies in multiple-case breast cancer families attending Familial Cancer Clinics in Australia and New Zealand. Methods The youngest affected woman, not known to carry a mutation in BRCA1 or BRCA2, from 747 multiple-case breast cancer families participating in kConFab were selected for PALB2 mutation screening. The coding and flanking intronic regions of PALB2 in DNA extracted from blood were screened using high-resolution melt curve analysis with Sanger sequencing confirmation. Where possible, relatives of women found to carry PALB2 mutations were genotyped for the family-specific mutation, mutant transcripts were characterised and breast tumours arising in mutation carriers were recalled and reviewed. Missense mutations were assessed for potential to disrupt protein function via SIFT, Align GVGD and Polyphen-2. Results The mutation screen identified two nonsense mutations (PALB2 c.3113G>A in eight women and PALB2 c.196C>T in one woman), two frameshift mutations (PALB2 c.1947_1948insA and PALB2 c.2982_2983insT each in one woman), 10 missense variants, eight synonymous variants and four variants in intronic regions. Of the four PALB2 mutations identified that were predicted to produce truncated protein products, only PALB2 c.1947_1948insA had not previously been reported. PALB2 c.3113G>A and PALB2 c.196C>T were previously identified in the Australian population whereas PALB2 c.2982_2983insT was previously reported in the UK population. Transcripts derived from three of these mutant PALB2 alleles were vulnerable to nonsense-mediated decay. One missense mutation (PALB2 c.2993G>A) was predicted to disrupt protein function via the three in silico assessment methods applied. The majority of breast cancers arising in carriers that were available for review were high-grade invasive ductal carcinomas. Conclusions: About 1.5% (95% CI 0.6to 2.4) of Australasian multiple-case breast cancer families attending clinics are segregating protein-truncating mutations in PALB2, most being PALB2 c.3113G>A, p.Trp1038*. Given the prevalence, breast cancer risk, and tumour grade associated with this mutation, consideration of clinical PALB2 testing is warranted.

Adjuvant!. Methods: Estimates for the prognostic effect of HER2 status were based on 14,017 breast cancer patients from 15 studies in the Breast Cancer Association Consortium. Relative hazard estimates for HER2 positivity were obtained separately for ER positive and ER negative disease and incorporated into Predict. The validation study comprised 1653 patients identified from the Breast Cancer Outcomes Unit (BCOU) database in British Columbia. 10-year predicted OS and BCSS were calculated for each patient using Predict+, Predict and Adjuvant! by investigators blinded to actual patient outcome. Predicted outcomes from all three models were compared with observed outcomes from the dataset. Results: The total number of deaths predicted by Adjuvant! (n¼492) was within 6.1% of that observed (n¼524) compared to 8.8% for Predict (n¼478) and 8.4% for Predict+ (n¼8.4). The total number of breast cancer specific deaths predicted by Adjuvant! (n¼311) was within 14% of that observed (n¼360) compared to 3.6% for Predict (n¼347) and 2.5% for Predict+ (n¼351). In patients with HER2 positive tumours (n¼203), the total number of breast cancer specific deaths predicted by Predict+ was within 4.0% of observed compared to 20% for Predict and 29% for Adjuvant!. Conclusion: This study reports the first clinical breast cancer prognostication tool (Predict) that includes HER2 status and demonstrated a marked improvement in 10-year BCSS estimates using Predict+ compared to the original Predict model and Adjuvant! for patients with HER2 positive tumours.

Background: Molecular tumor markers can be used to classify breast cancer into sub-types that have distinct survival patterns. It is not known whether these sub-types respond differently to adjuvant chemotherapy. The purpose of this study was i) to evaluate the prognostic significance of breast cancer sub-types in a cohort of women taking part in the NEAT and BR9601 clinical trials comparing cyclophosphamide, methotrexate, and fluorouracil (CMF) with ECMF (epirubicin and CMF) and ii) to evaluate whether the sub-types were predictive of the added benefit of epirubicin in these trials. Methods: We classified the tumors into six intrinsic sub-types using data generated from tumor tissue microarrays that were stained and scored for ER, PR, HER2, EGFR and CK5/6. We used Cox regression to compare relapse-free survival (RFS), breast cancer specific survival (BSS) and overall survival (OS) in the different subgroups. We also compared the effect of ECMF with CMF by subgroup. Results: IHC data were available for 1725 cases of whom 805 were luminal 1-basal negative, 153 were luminal 1-basal positive, 174 were luminal 2, 192 were HER2-like, 230 were core basal phenotype and 171 5-negative phenotype. Median follow-up time was 7 years. The prognostic effects of the sub-types were similar to those reported for unselected breast cancer cases irrespective of adjuvant therapy. In particular, the luminal 1-basal negative tumors were associated with the best prognosis during the five years after surgery and the HER2-like tumors were associated with the poorest prognosis. ECMF has previously shown to be associated with a 33 percent relative risk reduction for OS compared to CMF. There was little evidence for significant heterogeneity of effect by tumor subtype for any end point (OS P=0.40, BSS P=0.53 RFS P=0.50). However, there was an observed trend towards the largest additional benefit from epirubicin being in women with tumors of the 5-negative phenotype (OS HR=0.39 95% CI 0.21–0.73) and the smallest being in luminal 1-basal negative tumors (OS HR=0.86 95% CI 0.64–1.16). Conclusion: In a clinical trial in which all patients received chemotherapy, we confirmed that breast cancer sub-types show distinct behaviour with differences in short and long term survival. These differences seem to be independent of the type of chemotherapy - the benefit of ECMF over CMF was statistically similar in all disease sub-types. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C51.

12 Background: Breast cancer can be classified into molecular subtypes that have distinct survival patterns. The purpose of this study was i) to evaluate the prognostic significance of breast cancer subtypes in a cohort of women taking part in the NEAT and BR9601 clinical trials comparing CMF with ECMF, and ii) to evaluate whether the subtypes were predictive of the added benefit of epirubicin in these trials. Methods: Tumor tissue microarrays were stained and scored for ER, PR, HER2, EGFR and CK5/6. These were used to classify the tumors into six intrinsic subtypes (1). We used Cox regression to compare overall survival (OS), breast cancer specific survival (BSS) and relapse free survival (RFS) in the different subgroups. We also compared the effect of ECMF with CMF by subgroup. Results: IHC data were available for 1725 cases of whom 805 were Luminal 1-basal negative, 153 were Luminal 1-basal positive, 174 were Luminal 2, 192 were HER2-like, 230 were core basal phenotype and 171 were 5-negative phenotype. Median follow-up time was 7 years. The prognostic effects of the subtypes were similar to those reported for unselected breast cancer cases irrespective of adjuvant therapy (Blows FM, et al. PLoS Med 2010;75:e1000279.). In particular, the luminal 1-basal negative tumors were associated with the best prognosis in five years after surgery and the HER2-like tumors were associated with the poorest prognosis. ECMF has previously shown to be associated with a 33% relative risk reduction for OS compared to CMF (Poole CJ et al. N Engl J Med 2006;35518:1851-62.). There was little evidence for significant heterogeneity of effect by tumor subtype for any end point (OS P= 0.40, BSS P=0.53 RFS P=0.50). However, there was an observed trend towards the largest additional benefit from ECMF being in women with tumors of the 5-negative phenotype (OS HR=0.39 95% CI 0.21-0.73) and the smallest being in Luminal 1-basal negative tumors (OS HR=0.86 95% CI 0.64-1.16). Conclusions: In a clinical trial in which all patients received chemotherapy, we confirmed that breast cancer subtypes show distinct behaviour with differences in short and long term survival. The benefit of ECMF over CMF was statistically similar in all disease subtypes.

Background: Breast cancer is heterogeneous and the existing prognostic classifiers are limited in accuracy, leading to unnecessary treatment of numerous women. B-cell lymphoma 2 (BCL2), an antiapoptotic protein, has been proposed as a prognostic marker, but this effect is considered to relate to oestrogen receptor (ER) status. This study aimed to test the clinical validity of BCL2 as an independent prognostic marker. Methods: Five studies of 11 212 women with early-stage breast cancer were analysed. Individual patient data included tumour size, grade, lymph node status, endocrine therapy, chemotherapy and mortality. BCL2, ER, progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) levels were determined in all tumours. A Cox model incorporating the time-dependent effects of each variable was used to explore the prognostic significance of BCL2. Results: In univariate analysis, ER, PR and BCL2 positivity was associated with improved survival and HER2 positivity with inferior survival. For ER and PR this effect was time dependent, whereas for BCL2 and HER2 the effect persisted over time. In multivariate analysis, BCL2 positivity retained independent prognostic significance (hazard ratio (HR) 0.76, 95% confidence interval (CI) 0.66–0.88, P

522 Background: Neo-tAnGo used a 2-by-2 factorial design, addressing: (i) gemcitabine (G) in a sequential neoadjuvant chemotherapy (CT) regimen of epirubicin/cyclophosphamide (EC) and paclitaxel (T); and (ii) the sequencing of these treatment components (EC then T ± G versus T ± G then EC). Methods: Patients (Pts) with early breast cancer (T2 tumours or above) were randomised to EC then T, T then EC, EC then TG or TG then EC. All components were given x 4 cycles. (E= 90 mg/m2 day (d)1 every (q) 21d; C = 600 mg/m2 d1 q21d; T = 175 mg/m2 d1 q14d; G = 2,000 mg/m2 d1 q14d.) The primary endpoint was pCR, defined as absence of invasive disease in the breast and axillary lymph nodes. 800 pts were required to detect 10% differences in the primary endpoint pCR rates, at the 5% (2-sided) significance level with 85% power. Stratification was by age, inflammatory/locally advanced disease, tumour size, clinical involvement of axillary nodes and oestrogen receptor (ER) status. Results: Between January 2005 and September 2007, 831 pts were randomised by 88 consultants from 57 UK centres. Characteristics were balanced across groups: 63% [Table: see text]

Abstract #45 Background: The role of HER2 and Topoisomerase IIα (TOPO2α) as predictors of anthracycline sensitivity remains controversial. To address this we conducted an analysis of HER2, Topoisomerase IIα amplification (TOPO2α-amp) and deletion (TOPO2α-del), chromosome 17 polysomy (C17) and Ki67 as prognostic and predictive markers in the UK National Epirubicin Adjuvant Trial (NEAT) which compared classical CMF with Epirubicin followed by CMF (NEJM 2006;355:1851-62). Methods: TMAs constructed with 1638/2021 tumors from patients in the NEAT study were analysed for HER2/TopoIIα gene alterations, C17 polysomy, and Ki67. Log-rank analyses explored the prognostic value of markers on relapse-free survival (RFS) and overall survival (OS). Cox-regression models tested independent prognostic value on RFS and OS in the presence of treatment, age, type of surgery, tumor size, nodal status, ER status and grade, and marker x treatment interactions for RFS and OS. Results: Of 1625 NEAT samples analysed, 806(50%) received anthracycline-containing treatment; 985(61%) were ≤50 years old; 1114(69%) had nodal involvement; 791 (49%) were ER+ve; 961(59%) had G3 tumours; and 893 (56%) had tumour size >2cm. 19% were HER2-amp, 9% were TOPO2α-amp, 9% were TOPO2α-del, 18% were polysomic for C17 and 62% had high Ki67 (>13.0%). HER2-amp and TOPO2α-del were significant poor prognostic factors (P Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 45.

SummaryBackgroundAnthracyclines and taxanes have been the standard neoadjuvant chemotherapies for breast cancer in the past decade. We aimed to assess safety and efficacy of the addition of gemcitabine to accelerated paclitaxel with epirubicin and cyclophosphamide, and also the effect of sequencing the blocks of epirubicin and cyclophosphamide and paclitaxel (with or without gemcitabine).MethodsIn our randomised, open-label, 2×2 factorial phase 3 trial (Neo-tAnGo), we enrolled women (aged >18 years) with newly diagnosed breast cancer (tumour size >20 mm) at 57 centres in the UK. Patients were randomly assigned via a central randomisation procedure to epirubicin and cyclophosphamide then paclitaxel (with or without gemcitabine) or paclitaxel (with or without gemcitabine) then epirubicin and cyclophosphamide. Four cycles of each component were given. The primary endpoint was pathological complete response (pCR), defined as absence of invasive cancer in the breast and axillary lymph nodes. This study is registered with EudraCT (2004-002356-34), ISRCTN (78234870), and ClinicalTrials.gov (NCT00070278).FindingsBetween Jan 18, 2005, and Sept 28, 2007, we randomly allocated 831 participants; 207 received epirubicin and cyclophosphamide then paclitaxel; 208 were given paclitaxel then epirubicin and cyclophosphamide; 208 had epirubicin and cyclophosphamide followed by paclitaxel and gemcitabine; and 208 received paclitaxel and gemcitabine then epirubicin and cyclophosphamide. 828 patients were eligible for analysis. Median follow-up was 47 months (IQR 37–51). 207 (25%) patients had inflammatory or locally advanced disease, 169 (20%) patients had tumours larger than 50 mm, 413 (50%) patients had clinical involvement of axillary nodes, 276 (33%) patients had oestrogen receptor (ER)-negative disease, and 191 (27%) patients had HER2-positive disease. Addition of gemcitabine did not increase pCR: 70 (17%, 95% CI 14–21) of 404 patients in the epirubicin and cyclophosphamide then paclitaxel group achieved pCR compared with 71 (17%, 14–21) of 408 patients who received additional gemcitabine (p=0·98). Receipt of a taxane before anthracycline was associated with improved pCR: 82 (20%, 95% CI 16–24) of 406 patients who received paclitaxel with or without gemcitabine followed by epirubicin and cyclophosphamide achieved pCR compared with 59 (15%, 11–18) of 406 patients who received epirubicin and cyclophosphamide first (p=0·03). Grade 3 toxicities were reported at expected levels: 173 (21%) of 812 patients who received treatment and had full treatment details had grade 3 neutropenia, 66 (8%) had infection, 41 (5%) had fatigue, 41 (5%) had muscle and joint pains, 37 (5%) had nausea, 36 (4%) had vomiting, 34 (4%) had neuropathy, 23 (3%) had transaminitis, 16 (2%) had acute hypersensitivity, and 20 (2%) had a rash. 86 (11%) patients had grade 4 neutropenia and 3 (

TP53 overexpression is indicative of somatic TP53 mutations and associates with aggressive tumors and poor prognosis in breast cancer. We utilized a two-stage SNP association study to detect variants associated with breast cancer survival in a TP53-dependent manner. Initially, a genome-wide study (n = 575 cases) was conducted to discover candidate SNPs for genotyping and validation in the Breast Cancer Association Consortium (BCAC). The SNPs were then tested for interaction with tumor TP53 status (n = 4,610) and anthracycline treatment (n = 17,828). For SNPs interacting with anthracycline treatment, siRNA knockdown experiments were carried out to validate candidate genes. In the test for interaction between SNP genotype and TP53 status, we identified one locus, represented by rs10916264 (p(interaction) = 3.44 × 10-5; FDR-adjusted p = 0.0011) in estrogen receptor (ER) positive cases. The rs10916264 AA genotype associated with worse survival among cases with ER-positive, TP53-positive tumors (hazard ratio [HR] 2.36, 95% confidence interval [C.I] 1.45 - 3.82). This is a cis-eQTL locus for FBXO28 and TP53BP2; expression levels of these genes were associated with patient survival specifically in ER-positive, TP53-mutated tumors. Additionally, the SNP rs798755 was associated with survival in interaction with anthracycline treatment (p(interaction) = 9.57 × 10-5, FDR-adjusted p = 0.0130). RNAi-based depletion of a predicted regulatory target gene, FAM53A, indicated that this gene can modulate doxorubicin sensitivity in breast cancer cell lines. If confirmed in independent data sets, these results may be of clinical relevance in the development of prognostic and predictive marker panels for breast cancer., published version, peerReviewed

Recent studies have reported germline CDH1 mutations in cases of lobular breast cancer (LBC) not associated with the classical hereditary diffuse gastric cancer syndrome. A multidisciplinary workgroup discussed genetic susceptibility, pathophysiology and clinical management of hereditary LBC (HLBC). The team has established the clinical criteria for CDH1 screening and results’ interpretation, and created consensus guidelines regarding genetic counselling, breast surveillance and imaging techniques, clinicopathological findings, psychological and decisional support, as well as prophylactic surgery and plastic reconstruction. Based on a review of current evidence for the identification of HLBC cases/families, CDH1 genetic testing is recommended in patients fulfilling the following criteria: (A) bilateral LBC with or without family history of LBC, with age at onset CDH1 asymptomatic mutant carriers, breast surveillance with clinical examination, yearly mammography, contrast-enhanced breast MRI and breast ultrasonography (US) with 6-month interval between the US and the MRI should be implemented as a first approach. In selected cases with personal history, family history of LBC and CDH1 mutations, prophylactic mastectomy could be discussed with an integrative group of clinical experts. Psychodecisional support also plays a pivotal role in the management of individuals with or without CDH1 germline alterations. Ultimately, the definition of a specific protocol for CDH1 genetic screening and ongoing coordinated management of patients with HLBC is crucial for the effective surveillance and early detection of LBC.

Background:\ud Neoadjuvant breast cancer trials are important for speeding up the introduction of new treatments for patients with early breast cancer and for the highly productive translational research which they facilitate. Meta-analysis of trial data shows clear correlation between pathological response at surgery after neoadjuvant chemotherapy and longer-term outcomes at an individual patient level. However, this does not appear to be present on individual trial level analysis, when correlating improved outcome for the investigational arm for the primary endpoint (pathological response) with longer-term outcomes.\ud \ud Discussion:\ud The correlation between pathological response and longer-term outcomes in trials is dependent on many factors. These include definitions of pathological response, both complete and partial; assessment methods for pathological response at surgery; subtype and prognosis of breast cancer at diagnosis; number of patients recruited; adjuvant treatments; the mechanism of action of the investigational drug; the length of follow-up at the time of reporting; the definitions used in longer-term outcomes analysis; clonal heterogeneity; and new adaptive trial designs with additional neo/adjuvant treatments. Future developments of neoadjuvant breast cancer trials are discussed. With so many factors influencing the correlation of longer-term outcomes for trial-level data, we conclude that the main focus of neoadjuvant trials should remain the primary endpoint of pathological response.\ud \ud Summary:\ud Neoadjuvant breast cancer trials are very important investigational studies that will continue to increase our understanding of the disease and offer the potential of more rapid introduction of new treatments for women with high-risk early breast cancer. In the future, we are likely to see both novel trial designs adopted in the neoadjuvant context and modifications of neo/adjuvant treatments for pathological non-responders within clinical trials. Both of these have the intention of improving longer-term outcomes for patients who do not have a good pathological response to first-line neoadjuvant treatment. If successful, these developments are likely to reduce further any positive correlation between pathological response and longer-term outcomes.