Abstract Background: LORIS is a multi-centre, randomised (1:1) controlled trial of Surgery v Active Monitoring with annual mammography in patients with low risk ductal carcinoma in situ (DCIS). During a 2 year Feasibility Study potential patients were invited to complete the Clinical Trials Questionnaire (CTQ)1 and participate in a semi structured telephone interview about the verbal, written and DVD based trial information. The DVD was produced to complement the patient information sheet (PIS) and incorporates simple graphics and a Q&A session with women asking the Chief Investigator questions about the trial. Aims:To examine the reasons for trial participation/rejection and obtain feedback about the clarity, timing and usefulness of the PIS and DVD in order to identify potential communication drivers and barriers to trial recruitment. Methods: Participants completed the CTQ1 prior to randomisation and with their consent were contacted following randomisation for an interview. Women declining the trial were issued with an optional pack containing the CTQ1 and the researchers' contact details if they wanted an interview. The CTQ1 comprises16 reasons that might influence a decision to either accept or decline a trial. For each statement participants register their agreement or disagreement on a scale of 1 (strongly agree) to 5 (strongly disagree) and indicate the most important reason for their decision. Interviews explored factors such as, attitudes about randomisation, and usefulness of the trial information provided. Results: 41 patients were randomised during feasibility; 20 surgery, 21 active monitoring, 16 patients declined the trial. 40/41(98%) acceptors and 9/16 (56%) decliners completed the CTQ1. The main reason for joining LORIS was:- “I thought the trial offered the best treatment available” 13/40 (32%) and for decling the trial was “The idea of randomisation worried me” (4/9; 44%). 35 interviews were conducted (31/41 (76%) accepted and 4/16 (25%) declined LORIS). At interview acceptors commented that the PIS was very useful and clear (84%; 26/31 & 90%; 28/31, respectively). 74% (23/31) of women who joined LORIS watched the DVD and the majority (19/23; 83%) found it “very useful” and 22 (22/23; 96%) “very easy to understand”. A third of women (10/31) said the PIS and the DVD helped them decide to participate in LORIS. Women who declined the trial had clear treatment preferences; 2/4 did not watch the DVD. Three quarters of women interviewed (19/25) watched the DVD with family members/friends and found it reassuring. One commented it was “Put in words you can understand and not be baffled by”. The most popular aspect was the Q&A session (13/25; 52%). Conclusions:The LORIS DVD was a useful, easy to understand recruitment tool, complementing the PIS. Many women felt reassured that the content was consistent with, and added to that provided by healthcare professionals. Opinions of family and friends, worries about randomisation and personal preferences exert an influence of those declining these types of trial. Fallowfield LJ, Jenkins V, et al. (1998) Attitudes of patients to randomised clinical trials of cancer therapy. Eur J Cancer 34(10):1554–1559. Citation Format: Fallowfield LJ, Matthews L, Jenkins VA, May SF, Francis A, Rae D, Wallis M. Interview data from women contemplating LORIS trial entry during the feasibility study [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 OT3-08-01.

The 2013 Breast Cancer Campaign gap analysis established breast cancer research priorities without a specific focus on surgical research or the role of surgeons on breast cancer research. This Review aims to identify opportunities and priorities for research in breast surgery to complement the 2013 gap analysis. To identify these goals, research-active breast surgeons met and identified areas for breast surgery research that mapped to the patient pathway. Areas included diagnosis, neoadjuvant treatment, surgery, adjuvant therapy, and attention to special groups (eg, those receiving risk-reducing surgery). Section leads were identified based on research interests, with invited input from experts in specific areas, supported by consultation with members of the Association of Breast Surgery and Independent Cancer Patients' Voice groups. The document was iteratively modified until participants were satisfied that key priorities for surgical research were clear. Key research gaps included issues surrounding overdiagnosis and treatment; optimising treatment options and their selection for neoadjuvant therapies and subsequent surgery; reducing rates of re-operations for breast-conserving surgery; generating evidence for clinical effectiveness and cost-effectiveness of breast reconstruction, and mechanisms for assessing novel interventions; establishing optimal axillary management, especially post-neoadjuvant treatment; and defining and standardising indications for risk-reducing surgery. We propose strategies for resolving these knowledge gaps. Surgeons are ideally placed for a central role in breast cancer research and should foster a culture of engagement and participation in research to benefit patients and health-care systems. Development of infrastructure and surgical research capacity, together with appropriate allocation of research funding, is needed to successfully address the key clinical and translational research gaps that are highlighted in this Review within the next two decades.

Background: Precision medicine is heralded as offering more effective treatments to smaller targeted patient populations. In breast cancer, adjuvant chemotherapy is standard for patients considered as high-risk after surgery. Molecular tests may identify patients who can safely avoid chemotherapy. Objectives: To use economic analysis before a large-scale clinical trial of molecular testing to confirm the value of the trial and help prioritize between candidate tests as randomized comparators. Methods: Women with surgically treated breast cancer (estrogen receptor-positive and lymph node-positive or tumor size =30 mm) were randomized to standard care (chemotherapy for all) or test-directed care using Oncotype DX (TM). Additional testing was undertaken using alternative tests: MammaPrint (TM), PAM-50 (Prosigna (TM)), MammaTyper (TM), IHC4, and IHC4-AQUA (TM) (NexCourse Breast (TM)). A probabilistic decision model assessed the cost-effectiveness of all tests from a UK perspective. Value of information analysis determined the most efficient publicly funded ongoing trial design in the United Kingdom. Results: There was an 86% probability of molecular testing being cost-effective, with most tests producing cost savings (range -1892 to 195) and quality-adjusted life-year gains (range 0.17-0.20). There were only small differences in costs and quality-adjusted life-years between tests. Uncertainty was driven by long-term outcomes. Value of information demonstrated value of further research into all tests, with Prosigna currently being the highest priority for further research. Conclusions: Molecular tests are likely to be cost-effective, but an optimal test is yet to be identified. Health economics modeling to inform the design of a randomized controlled trial looking at diagnostic technology has been demonstrated to be feasible as a method for improving research efficiency. Copyright (C) 2017, International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc.

Abstract 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.

Breast cancer progression, treatment resistance, and relapse are thought to originate from a small population of tumor cells, breast cancer stem cells (BCSCs). Identification of factors critical for BCSC function is therefore vital for the development of therapies. Here, we identify the arginine methyltransferase PRMT5 as a key in vitro and in vivo regulator of BCSC proliferation and self-renewal and establish FOXP1, a winged helix/forkhead transcription factor, as a critical effector of PRMT5-induced BCSC function. Mechanistically, PRMT5 recruitment to the FOXP1 promoter facilitates H3R2me2s, SET1 recruitment, H3K4me3, and gene expression. Our findings are clinically significant, as PRMT5 depletion within established tumor xenografts or treatment of patient-derived BCSCs with a pre-clinical PRMT5 inhibitor substantially reduces BCSC numbers. Together, our findings highlight the importance of PRMT5 in BCSC maintenance and suggest that small-molecule inhibitors of PRMT5 or downstream targets could be an effective strategy eliminating this cancer-causing population.

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Oncology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Oncology journal

IMPORTANCE While the prevalence of ductal carcinoma in situ (DCIS) of the breast has increased substantially following the introduction of breast-screening methods, the clinical significance of early detection and treatment for DCIS remains unclear.OBJECTIVE To investigate the survival benefit of breast surgery for low-grade DCIS.DESIGN, SETTING, AND PARTICIPANTS A retrospective longitudinal cohort study using the Surveillance, Epidemiology, and End Results (SEER) database from October 9, 2014, to January 15, 2015, at the Dana-Farber/Brigham and Women's Cancer Center. Between 1988 and 2011, 57 222 eligible cases of DCIS with known nuclear grade and surgery status were identified.EXPOSURES Patients were divided into surgery and nonsurgery groups.MAIN OUTCOMES AND MEASURES Propensity score weighting was used to balance patient backgrounds between groups. A log-rank test and multivariable Cox proportional hazards model was used to assess factors related to overall and breast cancer-specific survival.RESULTS Of 57 222 cases of DCIS identified in this study, 1169 cases (2.0%) were managed without surgery and 56 053 cases (98.0%) were managed with surgery. With a median follow-up of 72 months from diagnosis, there were 576 breast cancer-specific deaths (1.0%). The weighted 10-year breast cancer-specific survival was 93.4% for the nonsurgery group and 98.5% for the surgery group (log-rank test, P < .001). The degree of survival benefit among those managed surgically differed according to nuclear grade (P = .003). For low-grade DCIS, the weighted 10-year breast cancer-specific survival of the nonsurgery group was 98.8% and that of the surgery group was 98.6%(P = .95). Multivariable analysis showed there was no significant difference in the weighted hazard ratios of breast cancer-specific survival between the surgery and nonsurgery groups for low-grade DCIS. The weighted hazard ratios of intermediate-and high-grade DCIS were significantly different (low grade: hazard ratio, 0.85; 95% CI, 0.21-3.52; intermediate grade: hazard ratio, 0.23; 95% CI, 0.14-0.42; and high grade: hazard ratio, 0.15; 95% CI, 0.11-0.23) and similar results were seen for overall survival.CONCLUSIONS AND RELEVANCE The survival benefit of performing breast surgery for low-grade DCIS was lower than that for intermediate-or high-grade DCIS. A prospective clinical trial is warranted to investigate the feasibility of active surveillance for the management of low-grade DCIS.

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Oncology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Oncology journal

Objectives: To investigate the radiological features, diagnosis and management of screen-detected lobular neoplasia (LN) of the breast.Materials and methods: 392 women with pure LN alone were identified within the prospective UK cohort study of screen-detected non-invasive breast neoplasia (the Sloane Project). Demography, radiological features and diagnostic and therapeutic procedures were analysed.Results: Non-pleomorphic LN (369/392) was most frequently diagnosed among women aged 50-54 and in 53.5% was at the first screen. It occurred most commonly on the left (58.0%; p = 0.003), in the upper outer quadrant and confined to one site (single quadrant or retroareolar region). No bilateral cases were found. The predominant radiological feature was microcalcification (most commonly granular) which increased in frequency with increasing breast density. Casting microcalcification as a predominant feature had a significantly higher lesion size compared to granular and punctate patterns (p = 0.034). 326/369 (88.3%) women underwent surgery, including 17 who underwent >1 operation, six who had mastectomy and six who had axillary surgery. Two patients had radiotherapy and 15 had endocrine treatment. Pleomorphic lobular carcinoma in situ (23/392) presented as granular microcalcification in 12; four women had mastectomy and six had radiotherapy.Conclusion: Screen-detected LN occurs in relatively young women and is predominantly non-pleomorphic and unilateral. It is typically associated with granular or punctate microcalcification in the left upper outer quadrant. Management, including surgical resection, is highly variable and requires evidence-based guideline development. (C) 2016 Elsevier Ltd. All rights reserved.

Abstract COX2 has been implicated in breast tumorigenesis, tumour proliferation & invasion. The role of COX2 in carcinogenesis is thought to be related to its abilities to increase production of prostaglandins, convert pro-carcinogens to carcinogens, inhibit apoptosis, promote angiogenesis, modulate inflammation & immune function & increase tumour cell invasiveness. COX2 inhibition may synergise with aromatase inhibition in controlling endocrine responsive breast cancer. The COX2 product prostaglandin E2 (PGE2) & cytokines such as interleukin-6 (IL6) can up regulate aromatase expression suggesting that aromatase inhibition may be more effective in combination with a COX2 inhibitor. There may be additional COX2 mediated anticancer activity. The hypothesis addressed is that activity of aromatase inhibitors(AI) as neoadjuvant endocrine therapy for early breast cancer may be enhanced by the addition of a COX2 inhibitor. TRIAL OBJECTIVES To determine whether the activity of AIs as neo-adjuvant endocrine therapy for ER positive breast cancer in postmenopausal women may be enhanced by the addition of the selective COX2 inhibitor celecoxib. TRIAL DESIGN Prospective phase III multicentre randomised trial. Patients were randomised to receive 16 weeks of exemestane 25 mg daily or letrozole 2.5 mg daily (open label) and celecoxib 400 mg twice daily or matched placebo (double blinded). Translational research tumour samples were collected before, during & after therapy. KEY ELIGIBILITY CRITERIA Post menopausal, ER positive, invasive cancer, 2cms or greater with calipers & visible on USS. PRIMARY OUTCOME MEASURE Objective clinical response to neoadjuvant treatment by RECIST criteria. RESULTS Primary Outcome; Response to treatment has been calculated for 266 patients (Table 1). Response rate was 73% in the celecoxib arm & 55% in the placebo arm (p=0.0022). The response rates 4 arm comparison are shown in Table 2. After adjustment for AI effect the significant difference in response rates remained (p=0.0023); the difference in response rates was greater in the exemestane treated group (29%) compared to the letrozole group (7%) although heterogeneity between AI arms was statistically non-significant (p=0.06). Table 1 Primary Outcome Results: response ratesOUTCOMEPLACEBO N (%)CELECOXIB N (%)TOTAL N (%)X2statisticP-valueRESPONSE73(55)97(73%)170 (64%)9.38820.0022NO RESPONSE60 (45%)36 (27%)96 (36%) TOTAL133133266 Table 2: Response Rates 4 Arm Comparison EXEMESTANELETROZOLERESPONSEPLACEBO n(%)CELECOXIB n(%)TOTAL n(%)PLACEBO n(%)CELECOXIB n(%)TOTAL n(%)RESPONSE33 (49)52(78)85(63)40(61)45(68)85(64)NO RESPONSE34(51)15(22)49(37)26(39)21(32)47(36)TOTAL67671346666132 Secondary outcome; There was an USS response rate of 42% v 37% for celecoxib & placebo arms respectively (p=0.2513) CONCLUSION The addition of the COX2 inhibitor celecoxib to an AI significantly & substantially increased the clinical response from 55% to 73%. Effect on tumour size assessed with USS is less marked with a non-significant increase in responses from 37% to 42%. This work was supported by CRUK: CRUK/06/005 and Pfizer. Citation Format: Rea D, Francis A, Poole C, Brookes C, Stein R, Bartlett J, Dunn J, Canney P, Sutton R, Daoud R, Hallissey M, Achuthan R, Grant M, Babrah J, Smith S, Fraser J, Desai A, Al Dubaisi M, Patel A, Bristol J, Chandrasekharan S, Prest C, Jewkes A. NEO-EXCEL phase III neoadjuvant trial of pre-operative exemestane or letrozole +/- celecoxib in the treatment of ER positive postmenopausal early breast cancer. [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 PD2-02.

The 2012 Breast Screening review acknowledged overtreatment of invasive screen detected breast cancer as well as DCIS. To inform the design of a possible clinical trial that could address this, an audit was undertaken to assess the concordance between diagnostic biopsies which were reported as grade 1 and the subsequent excision histology of these screen detected cancers.

Background: Randomized controlled trials (RCT) outcomes are a critical component of evaluating novel cancer surgeries. There are, however, unique challenges in selecting, measuring and reporting surgical outcomes that need to be addressed. This national workshop aimed to define future surgical outcomes research in this area.

Background: NICE guidelines on Familial Breast Cancer (FBC) were updated in 2013 and focus on classification and care of people at risk of FBC. This audit aimed to evaluate present Family History (FH) follow-up practice at University Hospital Birmingham (UHB), specifically looking at the referral to Clinical Genetics and surveillance strategies against the NICE Guidance.

BACKGROUND Previous reports identifying discordance between multiparameter tests at the individual patient level have been largely attributed to methodological shortcomings of multiple in silico studies. Comparisons between tests, when performed using actual diagnostic assays, have been predicted to demonstrate high degrees of concordance. OPTIMA prelim compared predicted risk stratification and subtype classification of different multiparameter tests performed directly on the same population. METHODS Three hundred thirteen women with early breast cancer were randomized to standard (chemotherapy and endocrine therapy) or test-directed (chemotherapy if Oncotype DX recurrence score >25) treatment. Risk stratification was also determined with Prosigna (PAM50), MammaPrint, MammaTyper, NexCourse Breast (IHC4-AQUA), and conventional IHC4 (IHC4). Subtype classification was provided by Blueprint, MammaTyper, and Prosigna. RESULTS Oncotype DX predicted a higher proportion of tumors as low risk (82.1%, 95% confidence interval [CI] = 77.8% to 86.4%) than were predicted low/intermediate risk using Prosigna (65.5%, 95% CI = 60.1% to 70.9%), IHC4 (72.0%, 95% CI = 66.5% to 77.5%), MammaPrint (61.4%, 95% CI = 55.9% to 66.9%), or NexCourse Breast (61.6%, 95% CI = 55.8% to 67.4%). Strikingly, the five tests showed only modest agreement when dichotomizing results between high vs low/intermediate risk. Only 119 (39.4%) tumors were classified uniformly as either low/intermediate risk or high risk, and 183 (60.6%) were assigned to different risk categories by different tests, although 94 (31.1%) showed agreement between four of five tests. All three subtype tests assigned 59.5% to 62.4% of tumors to luminal A subtype, but only 121 (40.1%) were classified as luminal A by all three tests and only 58 (19.2%) were uniformly assigned as nonluminal A. Discordant subtyping was observed in 123 (40.7%) tumors. CONCLUSIONS Existing evidence on the comparative prognostic information provided by different tests suggests that current multiparameter tests provide broadly equivalent risk information for the population of women with estrogen receptor (ER)-positive breast cancers. However, for the individual patient, tests may provide differing risk categorization and subtype information.

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 tumouru003e2cms 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.

Introduction: Over 19,000 patients undergo mastectomy per annum for invasive breast cancer or ductal carcinoma in situ (DCIS) in the UK. Several large published datasets have demonstrated considerable variation in mastectomy rates across UK. However, the reasons for this national variation remain unclear.

1570 Background: The degree of over-diagnosis and over-treatment for ductal carcinoma in situ (DCIS) remains contentious. Hypotheses from retrospective data were tested in a prospective, population-based study. Methods: A prospective longitudinal cohort of 12,838 women diagnosed through a population-based national breast screening program accrued 2003-2012 with proforma for imaging, surgery, pathology and adjuvant therapy. Follow-up was linked to national databases and case note review to analyse patterns of care, recurrence and mortality. Results: Data was complete for 9,972/12,838 (78%) women (mean age 60 years; range 46-87) with median follow up 62 months (range 6-116). Breast conservation (BCS) was definitive surgery for 7,028 (70.5%) women; use increased with older age (CHI2 380, 6 df p < 0.001). Mastectomy (Mx; n = 2,944) was associated with higher grade DCIS (CHI2 19.31, 2 df P < 0.001), larger size (CHI2 203.9, 5 df P < 0.001) and comedo necrosis (CHI2 9.1, 1 df P = 0.003). For patients undergoing BCS, use of radiotherapy was associated with high grade (CHI2 199.9, 2 df P < 0.001), comedo necrosis (CHI2 62.3, 1 df P = 0.001), larger size (CHI2 57.5, 5 df P < 0.001), microinvasion (CHI2 49.9, 1 df P = < 0.001), and use of endocrine therapy (CHI2 16.47, 3 df P < 0.001), but not close ( < 1mm) or involved margin(s). In women who underwent BCS, ipsilateral in-breast recurrence (n = 368; CHI2 27.14, 5 df P < 0.001) and ipsilateral invasive cancer (n = 182; CHI2 32.62, 5 df P < 0.001) were significantly reduced by radiotherapy, independent of margins. Endocrine therapy reduced local recurrence by 1.52%, independent of radiotherapy. Among 324 deaths (3.3% of the cohort), 47 were from invasive breast cancer. There was no difference in overall mortality by type of surgery (3.16% BCS vs 3.5% Mx; CHI2 0.017, 3 1f, P = 0.90), use of radiotherapy (2.48% or not 3.84%; CHI2 0.30, 1 df, P = 0.59) or endocrine therapy (3.88% or not 3.14%; CHI2 0.077, 1 df, P = 0.78). Conclusions: This prospective cohort of contemporary, screen-detected DCIS demonstrates ipsilateral recurrence, but not mortality, is reduced by radiotherapy and endocrine therapy. Death due to breast cancer was rare, outnumbered 5:1 by death from other causes.

Abstract Background: Multi-parameter gene expression assays (MPAs) are widely used to estimate individual patient residual risk and to guide chemotherapy use in hormone-sensitive HER2-negative node-negative early breast cancer. These uses of MPAs have not yet been prospectively validated. OPTIMA aims to validate the use of MPA testing to predict chemotherapy sensitivity in a largely node-positive breast cancer population. Methods: OPTIMA is a partially blinded multi-center, phase 3 randomized controlled trial with an adaptive two-stage design. The preliminary phase (OPTIMA prelim) evaluated the performance of MPAs to identify a suitable test(s) to be used in the main efficacy trial and assessed the feasibility and acceptability of a large UK trial. Eligible patients are men or women aged 40 years or older who have surgically resected early stage breast cancer, which is ER-positive and HER2-negative and who have either 1-9 involved axillary lymph nodes or tumors of at least 30mm diameter. Randomization is to standard management (chemotherapy followed by endocrine therapy) or to MPA-directed treatment. Those with a tumor categorized as "high-risk" by the test will be assigned to standard management whilst those at "low-risk" will be treated with endocrine therapy alone. OPTIMA prelim used Oncotype DX as the primary discriminator; the main trial will use Prosigna (PAM50). The co-primary outcomes are (1) Invasive Disease Free Survival (IDFS) and (2) cost-effectiveness of test-directed therapy compared to standard practice. Secondary outcomes include IDFS in "low-risk" patients, distant disease free survival, breast cancer specific survival, overall survival and quality of life. An integrated qualitative recruitment study will identify and address challenges to recruitment and informed consent. Tumor blocks from all consenting participants will be banked allowing the performance of alternative MPA technologies to be evaluated. Recruitment of 4500 patients over 4 years will permit demonstration of 3% non-inferiority of test-directed treatment, with 5% significance and 85% power, assuming 3 years follow-up and a control arm 5-year IDFS of at least 85%. The addition of patients from OPTIMA prelim will allow non-inferiority to be assessed with 2.5% significance. Results: OPTIMA-prelim recruited 412 patients in 23 months from 35 sites. It confirmed the acceptability of randomization to patients with a 47% acceptance rate, and to clinicians and hence the feasibility of a large prospective trial of test-directed treatment running in 100-plus UK sites. It showed that investment into research on test-directed therapy, especially with Prosigna, should be of substantial value to the NHS. Conclusion: OPTIMA, as one of two large scale prospective trials validating the use of test-guided chemotherapy in node-positive hormone-sensitive early breast cancer will have a global impact on patient treatment. Recruitment into the main efficacy trial will commence in October 2015. Funding: Project funded by the UK NIHR HTA Programme (10/34/501). Views expressed are those of the authors and not those of the HTA Programme, NIHR, NHS or the DoH. Citation Format: Stein RC, Marshall A, Hall PS, Bartlett JMS, Rooshenas L, Campbell A, Cameron DA, Rea D, Macpherson I, Earl HM, Poole CJ, Francis A, Morgan A, Harmer V, Pinder SE, Stallard N, Donovan J, Hulme C, McCabe C, Hughes-Davies L, Makris A, Dunn JA. OPTIMA (optimal personalised treatment of early breast cancer usIng multi-parameter analysis), a prospective trial to validate the predictive utility and cost-effectiveness of gene expression test-directed chemotherapy decisions. [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 OT3-02-12.

Multi-parameter gene expression assays (MPA) to aid selection of chemotherapy in hormone-sensitive early breast cancer have not been prospectively validated. This field of personalised medicine is rapidly evolving. There is currently no “best test”. OPTIMA is an adaptive trial of MPA-based chemotherapy assignment in a largely node-positive breast cancer population.