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Background Ductal carcinoma in situ (DCIS) now represents 20-25% of all breast neoplasia due to large-scale detection by widely adopted population-based breast cancer screening programs. As a result, thousands of women are confronted with DCIS each year: more than 8,000 in the UK, 2,500 in the Netherlands, and some 50,000 in the US. Conventional management includes surgery, supplemented by radiotherapy and/or endocrine therapy, but overtreats the majority of DCIS as ˜1% recur annually and breast cancer mortality is ˜3% at 20 years. Uncertainty as to which DCIS lesions will progress to invasive cancer or, after excision, which will return with recurrent DCIS or invasive breast cancer drives this overtreatment. This urges us to learn how to distinguish DCIS that may progress to invasive breast cancer from the majority of indolent DCIS. Such distinction may be best achieved by synergistic international collaboration between leading global experts from various disciplines, driven by the essential input from patient voices as full members of the research team. Aim PRECISION (PREvent ductal Carcinoma In Situ Invasive Overtreatment Now) aims to save thousands of women with low risk DCIS the burden of intensive inappropriate treatment of DCIS (surgery, radiation therapy, hormonal therapies) through the discovery of new data and development of novel tests that promote informed and shared decision-making between patients and clinicians, without compromising the excellent outcomes for DCIS management presently achieved. Methods First, three large DCIS cohorts and supplementary resources will be collected enabling in depth molecular studies. Second, extensive genomic characterization, immune profiling and imaging analysis will be performed. In vivo and in vitro modeling will be performed to study the biology of DCIS in detail. Finally, all clinical, immune, and molecular data will be incorporated into a clinical risk prediction model. This risk prediction model will be validated in three prospective randomized DCIS trials in the US (COMET trial), UK (LORIS trial), and mainland Europe (LORD trial). How the results of this research will be used The discoveries from our laboratory studies, including a risk stratification model, will be cross-validated in three prospective trials of DCIS active surveillance versus conventional treatment (the COMET, LORIS and LORD trials). As such, the main result of this study will be that we can identify a group of women for which active surveillance for DCIS could be a safer alternative to intensive treatment. Ultimately, this may also contribute to a more reassuring perception of risk regarding non-life threatening precancerous lesions in general, reducing anxiety and preserving quality of life. * The PRECISION Team is a Cancer Research UK Grand Challenge Award 2017 winning team and will be jointly funded by Cancer Research UK and the Dutch Cancer Society. Citation Format: Wesseling J, Thompson A, Nik-Zainal S, Futreal A, Hwang S, Jonkers J, Lips E, Rea D, On Behalf of the PRECISION Team. When is cancer not really cancer? The PREvent ductal carcinoma in situ invasive overtreatment now (PRECISION)* initiative [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P4-15-13.

BACKGROUND Patients receiving neoadjuvant chemotherapy for breast cancer go on to have surgery regardless of their response. Women with HER-2 positive ER negative tumours (7.5% of all operable breast cancers in the UK) respond so well to neoadjuvant treatment with dual anti-HER2 therapy in combination with chemotherapy that pathological complete response rates of 80% can be achieved. This means that for patients receiving this treatment surgery is being performed to remove a cancer that isn't there in the large majority. A study is planned in the UK (NOSTRA ) to assess if it is feasible to treat patients with HER-2 positive ER negative breast cancer who achieve a pCR after neoadjuvant chemotherapy with trastuzmab and pertuzumab with radiotherapy alone. The first phase of the trial will be a feasibility study commencing in 2017 where all patients will have image guided tumour bed biopsies post treatment and all patients will have surgery. If the group of patients where a pCR is achieved can be accurately identified then a phase III trial randomising to surgery and radiotherapy or radiotherapy alone is planned. The NOSTRA PRELIM study reported here assessed the ability of post neoadjuvant chemotherapy tumour bed biopsies to detect residual disease to provide experience to inform the much larger NOSTRA feasibility trial biopsy protocol. METHODS 23 consecutive patients with operable primary breast cancer scheduled for neoadjuvant chemotherapy were approached to take part in the study and 20 gave consent. All 20 patients had a clip inserted into the tumour bed under ultrasound(USS) guidance at diagnosis as is standard procedure. The number of cores taken ranged from 2-6. The median number of biopsies was 4 Tumour size range at diagnosis was 15-61mm with USS. All received neo-adjuvant chemotherapy and those who were Her2 positive received neoadjuvant trastusumab. At completion all patients had USS guided tumour bed biopsy. They then went on to have surgery, after which pathology was assessed and an RCB score calculated for each patient. For this study patients all tumour types were included as non pCR outcomes were required to determine accuracy and inform changes to the biopsy protocol for future use. RESULTS Only 2 patients in this study achieved a pCR Residual disease was correctly identified in 16/20 patients. Four patients had no tumour in their post treatment biopsies but had small residual invasive tumour at surgery. The size of residual disease in these patients ranged from 0.5 -9mm and all these patients had 3 core biopsies. One patient had negative post treatment biopsies and a PCR of their invasive tumour. This patient had a diagnostic biopsy that confirmed separate area of DCIS several centimetres from the invasive component. This area did not undergo post treatment tumour bed biopsies (although both areas were clipped at diagnosis). CONCLUSION A protocol for biopsy in the upcoming NOSTRA feasibility study has been designed to both take more biopsies and sample a larger area of the tumour bed in order minimise the false negative rate. Citation Format: Francis A, Herring K, Molyneux R, Jafri M, Trivedi S, Shaaban A, Rea DW. NOSTRA PRELIM: A non randomised pilot study designed to assess the ability of image guided core biopsies to detect residual disease in patients with early breast cancer who have received neoadjuvant chemotherapy to inform the design of a planned trial [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 P5-16-14.

Background: Marked variation in mastectomy rates exists across the UK. Identification of variation in practice is a key step towards standardisation of service. The rationale for advising mastectomy by multi-disciplinary teams (MDTs) has not been previously explored in the UK. The main aim of this multicentre observational study was to describe current practice in MDT decision-making for patients undergoing mastectomy. A secondary aim was to determine utilisation of neoadjuvant therapies. Methods: A multicentre, protocol-driven, prospective cohort study, led by trainees of the West Midlands Research Collaborative was performed during July and September 2015. Data was collected securely using Research Electronic Data Capture. Inclusion criteria were: women >18 years undergoing mastectomy for in situ/invasive disease; presenting with symptomatic or screen detected disease; performed as a primary procedure or following failure of breast conserving surgery (BCS); with or without immediate breast reconstruction (IR). Results: A total of 1776 patients (1823 mastectomies; 47 bilateral procedures) from 68 units were included. Median age was 63 years (range 20-99). In total 481 (26%) IRs were performed; median IR rate was 22% (range 0-67%). Mastectomy was advised by the MDT in 1402 (77%) cases. Reasons for advising mastectomy are shown in Table 1. Table 1. MDT rationale for advising mastectomyRationaleNumber of mastectomiesProportion (%)Large tumour to breast size ratio making BCS unsuitable53029.1Multi-centric disease on imaging37220.4Extensive malignant microcalcification1799.8Previous radiotherapy (Breast/Mantle)1638.9Requiring further surgery for positive margins following BCS1588.7Central tumour1136.2Large primary tumour, patient not suitable for neoadjuvant endocrine or chemotherapy treatment1126.1Neoadjuvant therapy failed to downsize tumour to allow BCS884.8Neoadjuvant therapy apparently successful but mastectomy advised anyway794.3Family History-High Risk512.8 In total 153 patients with oestrogen receptor positive (ER+) tumours were offered neoadjuvant endocrine treatment (NET); 131 (86%) received treatment. A total of 293 post-menopausal women with uni-focal, ER+ tumours, >20mm were not offered NET; mastectomy was advised by MDTs in 202 patients and the rationale for advising mastectomy in 173 patients (86%) was large tumour to breast size ratio. In total 104 patients with Human Epidermal Growth Factor Receptor 2 over-expressing (HER2+) tumours were offered neoadjuvant chemotherapy and trastuzumab (NACT); 89 (86%) received treatment. A total of 88 women 20mm were not offered NACT; mastectomy was advised by MDTs in 75 patients and rationale for advising mastectomy in 45 women (60%) was large tumour to breast size ratio. Conclusions: Although most mastectomies are advised for large tumour to breast size ratio, there is inconsistency in the utilisation of neoadjuvant therapies with many potentially eligible patients with large tumours not being given the opportunity to be downsized. Application of standardised recommendations for neoadjuvant treatment resulting in increased and appropriate use of neoadjuvant therapies could reduce the number of mastectomies advised by MDTs. Citation Format: Singh JK, McEvoy K, Marla S, Wilcox M, Rea D, Hallissey MT, Francis A, West Midlands Research Collaborative. Multicentre observational study evaluating why mastectomies are advised by UK multi-disciplinary teams [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 P3-13-05.

Background: The independent review of the UK National Health Service Breast Screening Programme reported (The Lancet, Volume 380, Issue 9855, Page 1778, 17 Nov 2012) on the benefits and harms of breast screening. It concluded that breast screening saves lives and acknowledged the existence of overtreatment. It encouraged randomized trials to elucidate the appropriate treatment of screen-detected DCIS to gain a better understanding of its natural history. The LORIS trial addresses the possible overtreatment of low and low/intermediate grade screen-detected (low risk) DCIS by randomizing patients to standard surgical treatment or active monitoring, each with long term follow up. Trial Design: LORIS is a phase III, multicentre, 2 arm study, with a built in 2 year Feasibility Phase, in patients confirmed to have low risk DCIS defined by strict criteria and determined by central pathology review. Patients will be randomized between standard surgery and active monitoring with annual mammography. Patients will be followed up for a minimum of 10 years. Eligibility Criteria: 1) Female, age ≥ 46 years 2) Screen-detected or incidental microcalcification (with no mass lesion clinically or on imaging) 3) Low risk DCIS on large volume vacuum-assisted biopsy, confirmed by central pathology review 4) Patient fit to undergo surgery 5) No previous breast cancer or ipsilateral DCIS diagnosis 6) Written informed consent Specific Aims: The LORIS Trial aims to establish whether patients with newly diagnosed low risk DCIS can safely avoid surgery without detriment to their wellbeing (psychological and physical) and whether those patients that do require surgery can be identified by pathological and radiological means. Primary endpoint: Ipsilateral invasive breast cancer free survival time Secondary endpoints: Overall survival; mastectomy rate; time to mastectomy; time to surgery; patient reported outcomes; health resource utilisation and assessment of predictive biomarkers. A digital image data repository and tissue bank will provide a prospective resource for both translational and imaging studies. Statistical Methods: A total of 932 patients will be randomized to a non-inferiority design to test the null hypothesis that active monitoring of women diagnosed with low risk DCIS is not non-inferior in terms of ipsilateral invasive breast cancer free survival (iiBCFS) time compared to treatment with surgery. The iiBCFS time will be compared across the two arms on a per protocol and intent-to-treat basis, using a 1-sided (α=0.05) log-rank test for non-inferiority. The iiBCFS rate is assumed to be 97.5% in the surgery arm at 5 years, utilizing 80% power to exclude a difference of more than 2.5% in the active monitoring arm. Present Accrual and Target Accrual: 32 UK centres are open for the Feasibility Phase of the trial which is nearing completion. The web-based central pathology review process is functioning efficiently, with a one week maximum turn around. Registrations and sites randomizing patients are on or above target. Randomizations are currently approximately 70% of target. A total of 60 centres will open in the main trial. Contact Information: For further information, please email the LORIS Trial Office LORIS@trials.bham.ac.uk. Citation Format: Francis A, Bartlett J, Billingham L, Bowden S, Brookes C, Dodwell D, Evans A, Fairbrother P, Fallowfield L, Gaunt C, Hanby A, Jenkins V, Matthews L, Pinder S, Pirrie S, Rea D, Reed M, Roberts T, Thomas J, Wallis M, Wilcox M, Young J. The UK LORIS trial: Randomizing patients with low or low intermediate grade ductal carcinoma in situ (DCIS) to surgery or active monitoring [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 OT1-03-01.

Background The immunotherapy has revolutionized the world of oncology in the last decades with considerable advantages in terms of overall survival in cancer patients. The association of Pembrolizumab and Trastuzumab was recently proposed in clinical trials for the treatment of Trastuzumab-resistant advanced HER2-positive breast cancer. Although immunotherapies are frequently associated with a wide spectrum of immune-related adverse events, the cardiac toxicity has not been properly studied. Purpose We studied, for the first time, the putative cardiotoxic and pro-inflammatory effects of Pembrolizumab associated to Trastuzumab. Methods Cell viability, intracellular calcium quantification and pro-inflammatory studies (analyses of the production of Interleukin 1β, 6 and 8, the expression of NF-kB and Leukotriene B4) were performed in human fetal cardiomyocytes. Preclinical studies were also performed in C57BL6 mice by analyzing fibrosis and inflammation in heart tissues. Results The combination of Pembrolizumab and Trastuzumab leads to an increase of the intracellular calcium overload (of 3 times compared to untreated cells) and to a reduction of the cardiomyocytes viability (of 65 and 20–25%, compared to untreated and Pembrolizumab or Trastuzumab treated cells, respectively) indicating cardiotoxic effects. Notably, combination therapy increases the inflammation of cardiomyocytes by enhancing the expression of NF-kB and Interleukins. Moreover, in preclinical models, the association of Pembrolizumab and Trastuzumab increases the Interleukins expression of 40–50% compared to the single treatments; the expression of NF-kB and Leukotriene B4 was also increased. Conclusion Pembrolizumab associated to Trastuzumab leads to strong cardiac pro-inflammatory effects mediated by overexpression of NF-kB and Leukotriene B4 related pathways.

Background Recently, the world of oncology has been revolutionized by immunotherapy which has shown considerable advantages in terms of overall survival in cancer patients. The association of Pembrolizumab and Trastuzumab was recently proposed in clinical trials for the treatment of Trastuzumab-resistant advanced HER2-positive breast cancer. Although immunotherapies are frequently associated with a wide spectrum of immune-related adverse events, the cardiactoxicity has not been properly studied. Methods In human fetal cardiomyocytes exposed to Trastuzumab and Pembrolizumab alone or in combination, we studied: the cell viability (through MTS assay), the quantification of intracellular calcium, Interleukin 1β, 6 and 8; the expression of NF-kB and Leukotrienes. Preclinical studies were also performed in C57BL6 mice dividing them in 4 groups (6/group: untreated mice (control) ; mice treated with Pembrolizumab at 10 mg/Kg for the first dose, followed by 5 mg/Kg dose every 5 days until the study end point, according to literature; mice treated with Trastuzumab at 10 mg/kg/day; mice treated with both drugs in combination. After the administration period, we analyzed the fibrosis and inflammation in heart tissues. Results The combination of Pembrolizumab and Trastuzumab increases the intracellular calcium overload (of 3 times compared to untreated cells) and reduces the cardiomyocytes viability (of 65 and 20-25%, compared to untreated and Pembrolizumab or Trastuzumab treated cells, respectively; p Conclusions The association of Pembrolizumab and Trastuzumab exerts pro-inflammatory and pro fibrotic effects in the heart; these effects are mainly mediated by overexpression of NF-kB and Leukotriene B4 related pathways and pro-inflamamtory cytokines. Legal entity responsible for the study The authors. Funding This work was funded by the “Ricerca Corrente” grant from the Italian Ministry of Health. Disclosure All authors have declared no conflicts of interest.

Background: SECRAB is a large multicentre randomised controlled trial designed to determine the optimal sequence of CT and RT for women with EBC. The second objective of this trial was to determine if CT and RT treatment modalities could be given together without increased toxicity or compromising either modality. See abstract no 851519 for details of CT and RT scheduling. Methods: Data on acute skin reaction was collected on completion of RT and graded as mild, moderate or severe. Late toxicity data was collected annually and included lymphoedema, telangiectasia, severe subcutaneous fibrosis, brachial plexopathy, rib fracture, ischaemic heart disease, symptomatic lung fibrosis, and clinical radiation pneumonitis. Results: Between Jul 98 and Mar 04, 2296 women were randomised. Acute toxicity data was collected on 2267 patients who received RT. The distribution of RT schedules was balanced across treatment arms, with the majority of patients (67%) receiving 40Gy/15F (15F). Significantly more patients in the Syn arm experienced a delay of >10 days in CT delivery (11% vs 5%, p < 0.0001). Very few patients experienced a >7 days delay in RT in either arm (Syn n=12 vs Seq n=3). In a sub-set of 880 patients dose intensity of CT was not significantly different between the two arms. Percentage skin toxicities for the Syn and Seq arms respectively were: None 22.9 vs 36.3; Mild 52.4 vs 48.1; Moderate 20.2 vs 13.6; Severe 3.8 vs 1.1. A significantly (p < 0.001) higher proportion of patients on the Syn arm suffered a moderate or severe skin reaction compared to those on the Seq arm. An unplanned exploratory analysis by duration of RT showed that patients receiving >15F (45Gy/20F or 50Gy/25F) had a significantly worse acute skin reaction than those receiving 15F (25% vs 16%, p=15F. Acute radiation pneumonitis was 0.3% in both arms (n=5 in total). Percentage late toxicities for the Syn and Seq arms respectively were not significantly different for: moderate/severe lymphoedema 6.1 (n=70) vs 5.5 (n=64); severe subcutaneous fibrosis 1.3 (n= 15) vs 0.6 (n=7); brachial plexopathy 0.2 (n=2) vs 0.1 (n=1); rib fracture 0.6 (n=7) vs 0.4 (n=5); ischaemic heart disease 0.4 (n=5) vs 0.4 (n=2); symptomatic lung fibrosis 0.3 (n=15) vs 0.3 (n=7); and late clinical radiation pneumonitis 0.1 (n=1) vs 0.1 (n=1). Howevermoderate/severe telangiectasia was 2.5% vs 1.3% in the Syn and Seq arms respectively (p =0.05). This difference was not seen in patients receiving 15F. Conclusions: The delivery of Syn CT-RT in the adjuvant treatment of EBC is associated with an increase in acute skin toxicity however the percentage of severe reactions is less than 5%. These skin reactions were seen predominantly in patients treated with concurrent RT (>15F). An increase in late skin telangiectasia was also seen in patients receiving >15F. There was no difference in other late toxicities recorded. Syn CT-RT is feasible in the adjuvant treatment of EBC and does not result in a reduction in dose intensity of delivered CT. The optimal schedule is 40Gy/15F which is now the standard regime used in the UK. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-11-05.

We previously reported high activity for oxaliplatin and a modified de Gramont regimen (OxMdG) in a single centre study of patients with metastatic colorectal cancer. We now report results with a further 56 patients treated at 14 centres. Low rates of grade 3 and 4 toxicity were seen, with no toxic deaths. Objective response rates were CR/PR=53%; NC=34.7%; PD=12.2%. Median time to progression was 8.3 months and overall survival was 14.5 months. This regimen is more convenient than those based around the conventional de Gramont regimen but is highly active and well tolerated; it forms part of a current UK MRC phase 3 trial.

Surgery is an obligatory component of treatment for early breast cancer. The last 20 years developments in systemic neoadjuvant therapy have progressively increased pathological complete response (pCR). Pathological complete response is associated with excellent prognosis especially for hormone receptor negative cancers. Therapeutic advances and recognition of the importance of pathological subtype in predicting pCR facilitate identification of subgroups with very high pCR rates. Treatment of HER2 positive hormone receptor negative cancers with combination chemotherapy and multiple targeted anti-HER2 agents results in consistently high pCR rates of 60-83%. Routine surgery in this setting where most patients have no potential to benefit is of questionable value and the option of omitting surgery in these patients should now be explored in a randomized trial. For HER2 positive disease not achieving pCR after neoadjuvant treatment the outcomes are poor. Trials are underway to determine if outcomes for these patients can be improved with alternative targeted therapy.

Background: Patients with high risk early breast cancer undergoing chemotherapy are frequently treated with both anthracycline and taxane-based chemotherapy exposing patients to multiple toxicities. Molecular predictors of response to specific chemotherapy agents are emerging. Abnormal duplication of the centromeric region of chromosome 17 (CEP17) and either Topoisomerase 2A (TOP2A) gene amplification or deletion, have been identified in a recent meta-analysis as potent markers of anthracycline sensitivity (Bartlett et al JCO 2015). The ROSCO study has been designed to prospectively test the utility of these markers to select anthracycline or taxane based chemotherapy in the neoadjuvant setting. Key entry criteria: Confirmed invasive breast cancer; centrally confirmed CEP17 duplication and TOP2A status; primary tumour>2cms or documented axillary node metastasis Exclusion criteria include breast cancer with good risk features i.e. Grade 1/2 ER PR rich (Q score 7/8), HER2 negative tumours. Study treatment: Patients will undergo central testing for CEP-17 and TOP2A and be randomised to 4 cycles of FEC100 (5-Flourouracil 500mg/m2 Epirubicin 100mg/m2 cyclophosphamide 600mg/m2) or 4 cycles of TC (Docetaxel 75mg/m2 Cyclophosphamide 600 mg/m2). Following chemotherapy patients will undergo surgical resection, (Institutional standard). Patients with residual invasive cancer will receive 4 cycles of the alternative chemotherapy to that received in the neoadjuvant setting. HER2 positive patients will receive concurrent trastuzumab and continue standard adjuvant trastuzumab. . Patients with biopsy proven axillary node metastases will undergo combined blue dye and radioisotope tracer guided sentinel lymph node biopsy (SLNB) and axillary lymph node clearance as a single procedure during breast surgery. Adjuvant endocrine and radiation therapy will be Institutional standard Endpoints: The primary endpoint is pathological complete response (no invasive disease in breast or axilla (pCR)). Secondary endpoints include: clinical and radiological response; rate of breast conservation; patient reported outcomes; safety, tolerability and long term outcomes. In patients with proven nodal involvement the false negative rate of a negative post treatment SLNB compared to axillary node clearance will be reported. Sample size and stratification: 1050 patients will be randomised in a 1:1 ratio stratified by nodal status, ER, HER2, and biomarker status (CEP-17 amplified or TOP2A amplified/deleted) vs normal (CEP-17 normal TOP2A normal). Analysis: The primary analysis will assess the interaction between the treatment effect and CEP17/TOP2A status to determine if a differential treatment effect exists between CEP17/TOP2A Normal and CEP17/TOP2A Abnormal patients. pCR will be analysed using a logistic regression model including co-variates for treatment, CEP17/TOP2A status and an interaction term of the two effects Sample size is based on the ability to detect an absolute improvement in pCR in the biomarker abnormal group from 21% in the TC treated group to 30% in the FEC treated group. With 90% power at 10% significance level. Contact Information: the ROSCO Trial Office ROSCO@trials.bham.ac.uk. Citation Format: Rea DW, Haywood L, Francis AM, Bowden SJ, Brookes CM, MacKenzie M, Cameron D, Stein R, Earl HM, Thomas J, Abraham J, Stanley A, Starczinski J, McGoldrick T, Treharne-Jones P, Billingham L, Bartlett JM. ROSCO: A randomised phase III, stratified CEP17/TOP2A biomarker trial of neo-adjuvant 5-flourouracil, epirubicin and cyclophosphamide vs docetaxel and cyclophosphamide chemotherapy. [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 OT3-02-02.

Background:\ud The National Epirubicin Adjuvant Trial (NEAT) and BR9601 trials tested the benefit of epirubicin when added to cyclophosphamide, methotrexate and 5-fluorouracil (E-CMF) compared with standard CMF in adjuvant chemotherapy for women with early breast cancer. This report details longer follow-up with interesting additional time-dependent analyses.\ud \ud Methods:\ud National Epirubicin Adjuvant Trial used epirubicin (E) 3-weekly for four cycles followed by classical (c) CMF for four cycles (E-CMF) compared with cCMF for six cycles. BR9601 used E 3-weekly for four cycles followed by CMF 3-weekly for four cycles, compared with CMF 3-weekly for eight cycles.\ud \ud Results:\ud In all, 2391 eligible patients were randomised and with a median 7.4-year follow-up, E-CMF confirmed a significant benefit over CMF in both relapse-free survival (RFS) (78% vs 71% 5 years RFS, respectively, hazard ratio (HR)=0.75 (95% CI: 0.65–0.86), P

and on the EndoPredict as well as on the MammaPrint test results were compared. In comparison to the clinical-pathological prognostic markers the EndoPredict would lead to a change of therapy in 36.4% (16/44). Conclusion: It was noticeable that the amount of recommendations for chemotherapy grew by one-third, which is in contrast to all studies published so far. One reason could be a selection bias of the sample cohort because of the high amount of tumours with a grading of 3. If the choice of therapy would base on the MammaPrint result the EndoPredict would lead to a change of therapy in 37.5% (15/40). Both tests lead to different risk classification in 34.2% of patients. Our results shed doubt on the reliability of the current gene expression tests. Follow-up of our patients for extended time periods will be necessary to properly assess the value of the assays. Disclosure of Interest: No significant relationships.

Background: The independent review of the UK National Health Service Breast Screening Programme reported recently on the benefits and harms of breast screening (The Lancet, Volume 380, Issue 9855, Pages 1778 - 1786, 17 November 2012). This concluded that breast screening saves lives but acknowledged the existence of overtreatment. Consequently, randomized trials were recommended to elucidate the appropriate treatment of screen-detected ductal carcinoma in situ (DCIS) and to gain a better understanding of its natural history. The LORIS trial will address these issues in low and low/intermediate grade screen detected (low risk) DCIS. Trial Design: LORIS is a phase III, multicentre, 2 arm study, with a built in 2 year feasibility phase, in women confirmed by central pathology review to have low risk DCIS. Comprehensive site training will be complimented by a patient friendly DVD designed to ensure consistent and appropriate use of terminology. Patients will be randomised between standard surgery and active monitoring with annual mammography. Follow-up will be for a minimum of 10 years. Eligibility Criteria: 1) Female, age ≥ 46 years 2) Screen-detected or incidental microcalcification (with no mass lesion clinically or on imaging) 3) Low risk DCIS on large volume vacuum-assisted biopsy, confirmed by central pathology review 4) Patient fit to undergo surgery 5) No previous breast cancer or DCIS diagnosis 6) Written informed consent Specific Aims: The LORIS Trial aims to establish whether patients with newly diagnosed low risk DCIS can safely avoid surgery without detriment to their wellbeing (psychological and physical) and whether those patients who do require surgery can be identified by pathological and radiological means. Primary endpoint: Ipsilateral invasive breast cancer free survival rate at 5 years Secondary endpoints: Overall survival; mastectomy rate; time to mastectomy; time to surgery; patient reported outcomes; health resource utilisation and assessment of predictive biomarkers. A digital image data repository and tissue bank will provide a prospective resource for both translational and imaging studies. Statistical Methods: A total of 932 patients will be randomized to a non-inferiority design to test the null hypothesis that active monitoring of women diagnosed with low risk DCIS is not non-inferior in terms of 5 year ipsilateral invasive breast cancer free survival (iiBCFS) rate compared to treatment with surgery. The iiBCFS rate will be compared across the two arms on a per protocol and intent-to-treat basis, using a 1-sided (α = 0.05) log-rank test for non-inferiority. The iiBCFS rate is assumed to be 97.5% in the surgery arm giving 80% power to exclude a difference of more than 2.5% in the active monitoring arm at 5 years. Present Accrual and Target Accrual: 20 UK sites have been identified to contribute to the feasibility phase of the trial. Enrolment of the first patient is expected in late 2013/early 2014. A further 40 sites will be recruited upon successful completion of the feasibility phase. For further information, please contact the LORIS Trial Office LORIS@trials.bham.ac.uk. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT2-3-01.

Background SECRAB, a randomised trial comparing sequential (Seq) to synchronous (Syn) chemo-radiation using a CMF or Anthracycline-CMF regimen, demonstrates reduces local recurrence rates after Syn treatment for early breast cancer (EBC) (Fernando 2011 EJC:47 S2). Cosmesis study results are presented. Methods 2296 women were randomised and cosmesis was assessed in 382. Cosmesis and telangiectasia were assessed as excellent, good, moderate and poor for patients having wide local excision (WLE) while telangiectasia alone was assessed for those having mastectomy. Photographs were taken for 301 patients for blinded independent review using a consensus method (Haviland 2008 Clin Oncol 20:497). Patient perception was assessed using EORTC BR23 quality of life questionnaire (Q 39-42). Assessments were made at baseline, 1, 2 and 5 years post surgery. Results The results of clinician assessed cosmesis and telangiectasia are shown below. There was no statistically significant difference between the arms Table: 253PD Category Odds Ratio (OR) Excellent Good Moderate/Poor (95% CI) Seq Syn Seq Syn Seq Syn Excellent/good vs moderate/poor Cosmesis, n (%) 14 (23) 15 (21) 37 (60) 37 (51) 11 (18) 21 (29) 1.87, (0.82,4.27) p = 0.1 Telangiectasia, n (%) 79 (68) 99 (62) 33 (28) 54 (34) 4 (4) 7 (4) 1.28, (0.37,4.48) p = 0.7 Data on independent assessment of change in breast appearance after WLE was available for 145 (98%) patients. Minimal, mild and marked changes were observed in 70, 29 and 1% of patients respectively for the Syn arm and 72, 28 and 0% for the Seq arm. There was no difference between treatment arms (OR, mild/marked vs minimal, 1.10, 95% CI 0.54-2.26, p = 0.8). There was no change in patient's perception of their breast appearance (baseline vs. final assessment questionnaire). Conclusions There was no significant difference in cosmesis or telangiectasia between the two arms as assessed by the clinician or by independent photographic review. There was no difference in patient perception of breast appearance. Contrary to the result of the main study, which showed a borderline significant worsening of telangiectasia in the Syn arm, no such difference was seen in the cosmesis study. Syn chemo-radiation reduces local recurrence in EBC without affecting cosmesis. Disclosure All authors have declared no conflicts of interest.

Background: The TEAM (Tamoxifen Exemestane Adjuvant Multinational) trial is a contemporary multinational study of the effects of 5 years of adjuvant hormonal therapy, either exemestane (E) or tamoxifen switching to E (TàE). Five-year results were presented at SABCS 2009 showing no difference in outcome between E vs TàE (Rea D, SABCS Abstract 11), thus giving us the opportunity to analyze the causes of mortality in the entire population of 9766 women. Methods: Postmenopausal women with hormone receptor positive (HR+) early breast cancer (BC) were randomized to E or TàE for 5 years after completion of surgery, adjuvant chemotherapy (when indicated), and radiation therapy based on local guidelines. All data were collected and analyzed at the Central Data Center in Leiden. The primary outcome of DFS as well as safety and other secondary outcomes were analyzed in 2009 after 1285 events had occurred to trigger the analysis. Results: Between 2001 and January 2006, 9766 women were randomized; 100% were HR+, 50% had node negative disease, 68% received adjuvant radiotherapy, and 36% received adjuvant chemotherapy. The median follow-up was 5.1 years with over 60% of women having been followed for 5 or more years. Among 961 deaths, 568 (59%) were caused by BC and 393 (41%) by causes other than BC. The cumulative incidence of death from BC vs. other causes at 5-years for all women and by nodal status is as follows (see table): There was a general relationship with non-breast cancer deaths and increasing age at diagnosis (≥70 years), as expected. Non-breast cancer causes of mortality included second malignancy (105); cardiac (71), cerebral (33), or pulmonary (28) events; miscellaneous other causes (105); and unknown (51). Conclusions: Among 9766 postmenopausal women with HR+ BC treated with contemporary hormonal strategies following standard primary treatment, the probability of death from causes other than BC was nearly as high as the probability of dying from BC. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr PD08-03.

1052 Background: Aromatase inhibitors (AI) block estrogen synthesis and are effective for the treatment of estrogen receptor (ER) positive breast cancer in postmenopausal women. Despite initial benefit, resistance to AIs and disease progression occur, at which point cytotoxic chemotherapy is often the remaining treatment option. Entinostat, an oral class 1 isoform-selective HDACi, has been shown in preclinical studies to restore sensitivity to acquired AI resistance. The goal of this study was to determine whether the addition of entinostat to AI therapy in patients currently progressing on AI therapy could restore AI sensitivity and prolong the clinical benefit. Methods: Postmenopausal women with ER+ breast cancer progressing on an AI after 3 months were enrolled. Additional entry criteria included measurable disease by RECIST and ≤1 chemotherapy for metastatic disease. Patients with rapidly-progressive breast cancer were excluded. Patients continued with the AI on which they progressed plus entinostat 5...

Background: Exemestane (E) is a steroidal aromatase inhibitor (AI) with an established role in early breast cancer after 2–3 years of tamoxifen (T). Additionally, AIs have shown superiority to T as initial adjuvant therapy. The Tamoxifen Exemestane Adjuvant Multinational (TEAM) study has been prospectively designed to compare the role of E as initial adjuvant therapy with a sequential approach of T followed by E (T→E).Methods: Postmenopausal patients with hormone receptor–positive early breast cancer were randomized to open-label E 25 mg/d or T 20 mg/d. All patients completed surgery and chemotherapy, if indicated. Data were collected and analyzed by the Central Data Center in Leiden, The Netherlands. The trial was initiated in 2001 with the primary objective being a comparison of disease-free survival (DFS) with T vs E. In 2004, TEAM was modified in response to new data; all those initially receiving T were switched to E after 2.5–3 years. An additional 2500 patients were recruited and randomized at diagnosis to E or T→E for 5 years. The modified study design includes 2 coprimary endpoints: (1) DFS of T vs E that was previously reported at 2.75 years median follow-up (Jones S et al, abstract #15 presented at SABCS 2008); and (2) DFS at 5 years of E vs T→E that will be the focus of results presented here.Results: Between 2001 and January 2006, 9775 women were randomized to TEAM. In total, 99% of patients were ER+ and/or PgR+, 50% were node-negative, 44% underwent mastectomy, 68% received radiotherapy, and 36% received chemotherapy. In September 2009, median follow-up will be 5.5 years and the protocol-specified 1285 overall DFS events (locoregional or distant recurrence, second breast cancers, or death without recurrence) will have occurred, allowing for analysis of the second coprimary endpoint. We will present a detailed analysis of the 5-year results from theTEAM trial, the only prospectively powered randomized trial to compare 5 years of an initial AI vs T→AI, 2 commonly received adjuvant therapies for women with hormone receptor–positive early breast cancer. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 11.

Background: In ER+ early breast cancer, 5 years of tamoxifen substantially reduces the annual recurrence rate throughout the first decade (years 0-9). Despite this, appreciable risks of recurrence remain, with similar annual recurrence risks for ER+ disease during years 0-4, 5-9 and 10-14 following surgery. It is not reliably known how 10 years duration of adjuvant tamoxifen compares with the current standard of 5 years. Methods: Between 1991 and 2005, 6,934 women with ER+ (39%), or ER untested (61%) invasive breast cancer (53% node negative, 31% node positive, 16% node status unspecified) from 176 UK centers, who had completed 4+ years of adjuvant tamoxifen, were randomized between continuing for another 5 years and stopping. Information on compliance, hospital admission(s), breast cancer recurrence (including new contralateral disease), other new primary cancer, death and cause of death was sought annually. Results: 78% of those allocated to continue and 3% of those allocated to stop were taking adjuvant tamoxifen at 3 years following randomization; fewer than 1% switched to any other adjuvant hormone treatment. With a median follow-up of 4.2 years, there were fewer recurrences (415 vs 442; RR=0.94, 95% CI 0.81-1.09; p=0.4) among those allocated to 10yrs than 5yrs tamoxifen. Although breast cancer mortality was lower among those allocated 10yrs, with just 374 deaths from breast cancer recorded, data remain immature. Despite a doubling in the risk of endometrial cancer (76 vs 35) with 10yrs tamoxifen, there was no increase in deaths from endometrial cancer (10 vs 12) or from any other non-breast cancer cause. Conclusions: Although no significant reduction in recurrence has yet been seen in aTTom, the results are consistent with preliminary findings from the ATLAS trial, which reported a DFS but not overall survival advantage to longer tamoxifen (Peto et al SABCS 2007). Combining results from these two large studies indicate that continuation of tamoxifen beyond the first 5 years reduces recurrence over the next few years, but further follow-up is needed to assess reliably the longer-term effects on recurrence and the net effects, if any, on mortality.

11001 Background: E-CMF [epirubicin (E) x 4 cycles every (q) 21 days (d), followed by classical CMF x 4 cycles q 28d] is established as highly effective adjuvant chemotherapy for early breast cancer (BC), reducing mortality by 30% compared with CMF alone [Poole NEJM 2006]. However, dose dense anthracycline-taxane schedules, accelerated with GCSF support, have been shown to be superior to conventional regimens [Citron JCO 2003, Burnell SABCS 2006]. Exploration of accelerated E-CMF is therefore of considerable interest. Methods: A non-randomised, multicenter trial was designed to explore the feasibility and tolerability of accelerated E-CMF chemotherapy for women with early BC. The primary endpoint was delivered dose intensity (DDI). The accrual target was 40 patients (pts). Pts were treated with 4 cycles E (100mg/m2) q 14d, with Pegfilgrastim (PF) (6mg sc) d2, followed by 4 cycles of Cyclophosphamide, Methotrexate, and 5-Fluorouracil (600/40/600mg/m2) administered intravenously d1 + 8, with PF d9, q 21d. Results: 44 pts were enrolled. Complete dose information from 40 pts and toxicity data from 336 cycles (44 pts) has been analysed. Median DDI was 96.7% of target. Delays of >2 d were recorded for 8% of cycles. Dose reductions were recorded in 4% of cycles. 90% of pts received >85% intended total dose and 85% of pts received >85% intended DDI. Percentage grade 2 and 3/4 toxicity reported per cycle were respectively: fatigue 34/12; all infections 7/4; emesis 19/4; bone pain 18/4; diarrhoea 7/3; dyspnoea 20/3; febrile neutropenia not applicable (na)/2; mucositis 12/0.3; and phlebitis 29/na. Hospitalisation occurred in 10% of cycles. One pt developed endocarditis in association with repeated line infections, and a further pt experienced severe delayed phlebitis requiring surgical intervention. Conclusions: Accelerated E-CMF with PF is feasible achieving high DDI in a majority of pts. Non-haematological toxicity was responsible for the majority of hospital admissions which were more frequent than anticipated. Relative efficacy of this regimen requires phase III evaluation. We have also completed a second study of accelerated E-CMF where 6 cycles of intensified CMF (800/50/600mg/m2) was delivered at 14 d intervals. No significant financial relationships to disclose.