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Introduction Definition of the tumor bed (TB) is currently guided by intraoperatively placed metal clips. However, this traditional planning method may not be sufficient for tumor cavity defect refilled with modern oncoplastic breast surgery. We explored the impact of a close cooperation between surgeon and oncologist on the accuracy of TB contouring after partial breast reconstruction with chest wall perforator flaps (CWPF). Patients and Methods A retrospective review of patients who received radiotherapy after CWPF was performed. TB and boost volume were defined by the surgeon, considering clips and the typical radiologic appearance of the flap, and by a radiation oncologist, and results were compared with the surgical specimen volume (SPV). The boost volume was marked as 5 mm penumbral ring thickness of native breast tissue wall around the replaced flap (nonbreast tissue). Results There were no significant differences between SPV and surgeon-defined TB values. Conversely, the radiation oncologist–defined values were significantly smaller than the actual SPV. If a ring-shaped TB boost was delivered, this would have allowed a potential reduction of irradiated tissue of 127.6%. Conclusion TB definition solely by surgical clips may be prone to inaccuracy in case of volume replacement oncoplastic breast surgery. Our approach of combining the clips with the redefinition of the flap on computed tomographic scan may provide more accurate TB definition. Although an ideal ring-shaped boost might be difficult to reproduce in practice, it introduces a new paradigm: a lower radiation dose inside TB is tolerable, if not desirable, at least in CWPF.

Background: Multi-parameter tumour gene expression assays (MPAs) are widely used to estimate individual patient risk and to guide chemotherapy use in hormone-sensitive, HER2-negative early breast cancer. The TAILORx trial supports MPA use in a node-negative population. Evidence in node-positive breast cancer is limited. OPTIMA (Optimal Personalised Treatment of early breast cancer usIng Multi-parameter Analysis) (ISRCTN42400492) is a prospective international randomised controlled trial (RCT) designed to validate MPA’s as predictors of chemotherapy sensitivity in a largely node-positive breast cancer population. Methods: OPTIMA is a partially blinded study with an adaptive two-stage design. The main eligibility criteria are women and men age 40 or older with resected ER-positive, HER2-negative invasive breast cancer and up to 9 involved axillary lymph nodes. Randomisation is to standard management (chemotherapy and endocrine therapy) or to MPA-directed treatment using the Prosigna (PAM50) test. Those with a Prosigna tumour Score (ROR_PT) >60 receive standard management whilst those with a low score (≤60) are treated with endocrine therapy alone. Endocrine therapy for pre-menopausal women includes ovarian suppression. Prosigna tests are currently performed only for participants randomised to MPA-directed treatment. More than 1 tumour may be tested if participants have multi-focal tumours with discordant features and/or are considered clinically significant. The co-primary outcomes are: (1) Invasive Disease Free Survival (IDFS) and (2) cost-effectiveness. Secondary outcomes include IDFS in patients with low-score tumours and quality of life. Recruitment of 4500 patients over 5 years will permit demonstration of 3% non-inferiority of test-directed treatment, assuming 5-year IDFS of 85% with standard management. An integrated qualitative recruitment study addresses challenges to consent and recruitment, building on experience from the feasibility study which found that a multidisciplinary approach is important for recruitment success. Results: The OPTIMA main trial opened in January 2017. Overall recruitment as of 1 July 2019 was 1123 (1100 from UK, 13 from Norway); 91% had axillary node macro-metastases. Median time from consent to treatment allocation was 12 days (interquartile range 10-14 days). The withdrawal rate from trial treatment is 3%; 50% of these continue with follow up. Prosigna tests have been performed on 608 tumours for 549 participants; 59% were luminal A, 38% were luminal B and 3% non-luminal (6 patients with non-luminal tumours [1% overall] were ineligible on receptor retesting). Of the 53 (10%) participants with >1 tumour tested, 3 (6%) had discordant scores only, 7 (13%) had discordant subtypes only and 8 (15%) had both discordant scores and subtypes. Two thirds of the MPA-directed arm participants have been allocated to endocrine therapy only. The test failure rate is Conclusion: OPTIMA is one of two large scale prospective trials validating the use of test-guided chemotherapy decisions in node-positive early breast cancer. It is expected to have a global impact on breast cancer treatment. Funding: OPTIMA is 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 Department of Health. Trial Inquiries: OPTIMA@warwick.ac.uk Citation Format: Robert C Stein, Andrea Marshall, Andreas Makris, Luke Hughes-Davies, Iain R MacPherson, Carmel Conefrey, Leila Rooshenas, Sarah E Pinder, Abeer M Shaaban, Bjørn Naume, David A Cameron, Daniel W Rea, Helena M Earl, Christopher J Poole, Peter S Hall, Georgina Dotchin, Stuart A McIntosh, Victoria Harmer, Adrienne Morgan, Bethany Shinkins, Nigel Stallard, Christopher McCabe, Jenny L Donovan, John MS Bartlett, Janet A Dunn. OPTIMA: A prospective randomized trial to validate the clinical utility and cost-effectiveness of gene expression test-directed chemotherapy decisions in mostly node-positive early breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT3-17-01.

Background: Triple negative breast cancers (TNBCs) are an aggressive and diverse subgroup with no specific targeted therapies currently available. Basal TNBCs show some phenotypic and molecular similarities with germline BRCA mutated BC (gBRCA). In gBRCA patients, and potentially other homologous recombination deficiencies, these already compromised pathways may allow PARP inhibitors (olaparib) to work more effectively. PARTNER was designed to establish if the addition of olaparib to neoadjuvant platinum-based chemotherapy for gBRCA and/or basal TNBC is safe and improves efficacy (pathological complete response (pCR)). This is the first time a clinical trial provides safety data of the combination of olaparib with platinum and taxane chemotherapy in an early breast cancer setting. Methods: PARTNER is a 3-stage open label randomised Phase II/III trial of neoadjuvant Carboplatin AUC5 with weekly Paclitaxel 80mg/m2 (CP) +/- olaparib (O) 150mgBD for 12 days x 4 cycles, followed by clinicians' choice of anthracycline regimen x 3 cycles. Basal-TNBC and/or gBRCA patients are eligible for inclusion. Primary endpoints are defined by stage: Stage 1 - Safety, Stage2 - Schedule selection, and Stage 3 - Efficacy (pCR rate). The trial is now powered for efficacy analysis in the BRCA and non-BRCA population independently. Stage 1 and 2 randomization was(1:1:1) to CP: CP + O from day (D) -2: or CP + O from D 3. G-CSF was mandatory during the first 4 cycles of treatment. We present a pooled-safety analysis from Stage 1 and 2 of the two research arms only. Recruitment continues into Stage 3. Results: Between June 2016 and April 2018, 159 patients were recruited among the three arms. Overall, median age was 48.2 [range 22.3- 70.9]; 12% had Tumours >5cm, 34% had Axillary involvement; 17% were gBRCA. Adverse events (AE) that were reported as common (in at least 10% of patients) were Anaemia 23%, Neutropenia 18% and Infection 10%. Fatigue and Diarrhoea were next most prevalent with 9% and 6% respectively. The most common AE Grade >=3 were haematological events. These include Neutropenia 19%, Anaemia 15%, and Thrombocytopenia 5%. Febrile Neutropenia and Haemorrhage were reported in only 2% and 1% of cases. Grade 3 Non- haematological events were Fatigue 7%, Hypertension 3%, Headache 3% and Diarrhoea 2%. Grade 3 Sensory neuropathy was present in 2% of patients. No grade 4 sensory or motor neuropathy events were described. Serious adverse reactions related to investigational regimen were reported in 17% of patients and include fever and infection with 8 and 4 events respectively. No toxicity related deaths were reported. As per July 8th 2019, 373 patients have been recruited from which 58 were gBRCA. Conclusions: Combinations of olaparib with neoadjuvant CP chemotherapy showed an acceptable and manageable toxicity profile. Although haematological events were the most common, they did not exceed historical frequencies reported for standard chemotherapy regimens. Final safety analysis will be performed once recruitment is complete and will include detailed long-term neuropathy data. Citation Format: Karen Pinilla Alba, Emma McMurtry, Anne-Laure Vallier, Louise Grybowicz, Ellen Copson, Anne Armstrong, Rebecca Roylance, Wendi Qian, Nikolaos Demiris, Stanly Thomas, Caron Harvey, Luke Hughes-Davies, Karen McAdam, Paula del Rosario, Bryony Harrop, Elena Provenzano, Marc Tischkowitz, Helena M Earl, Jean E Abraham. Preliminary safety data from stage 1 and 2 of the phase II/III PARTNER trial: Addition of olaparib to platinum-based neoadjuvant chemotherapy in triple negative and/or germline BRCA mutated breast cancer patients [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-10-05.

Background:Multi-parameter tumour gene expression assays (MPAs) are widely used to estimate individual patient residual risk and to guide chemotherapy use in hormone-sensitive, HER2-negative early breast cancer. The TAILORx trial supports MPA use in a node-negative population. Evidence for MPA use in node-positive breast cancer is limited. OPTIMA (Optimal Personalised Treatment of early breast cancer usIng Multi-parameter Analysis) (ISRCTN42400492) aims to validate MPAs as predictors of chemotherapy sensitivity in a largely node-positive breast cancer population where prospective RCT (Randomised Controlled Trial) evidence is lacking. Methods: OPTIMA is a partially blinded multi-center RCT with an adaptive two-stage design. The main eligibility criteria are women and men age 40 or older with resected ER-positive, HER2-negative invasive breast cancer and up to 9 involved axillary lymph nodes. Randomisation is to standard management (chemotherapy and endocrine therapy) or to MPA-directed treatment using the Prosigna (PAM50) test. Those with a Prosigna tumour score (ROR_PT) >60 receive standard management whilst those with a low score (≤60) are treated with endocrine therapy alone. Endocrine therapy for pre-menopausal women includes ovarian suppression. The co-primary outcomes are (1) Invasive Disease Free Survival (IDFS) and (2) cost-effectiveness of test-directed treatment. Secondary outcomes include IDFS in patients with low-score tumours and quality of life. An integrated qualitative recruitment study addresses challenges to consent and recruitment and will build on experience from the feasibility study that a multidisciplinary approach at sites is important for recruitment success. Tumour blocks will be banked to allow evaluation of additional MPA technologies. Recruitment of 4500 patients over 5 years will permit demonstration of 3% non-inferiority of test-directed treatment, assuming 5-year IDFS of 85% with standard management, equivalent to a HR of 1.22. Inclusion of patients from the feasibility study will increase the power to test for non-inferiority. Results: The OPTIMA main trial opened in January 2017. Overall recruitment (including the feasibility study) will reach 1000 in August 2018. Recruitment in Norway will commence in July 2018. Characteristics of the OPTIMA main participants recruited to 31st May 2018 are shown in the table. Main study patient characteristicsCharacteristic %Median age in years (range)57 (40-80) Menopause statusPre34 Post66 Male1Tumour size=30mm42Node statuspN04 pN1mi(sn)7 pN1(sn)20 pN155 pN214Historic grade16 258 336 Conclusion: OPTIMA is one of two large scale prospective trials validating the use of test-guided chemotherapy decisions in node-positive early breast cancer. It is expected to have a global impact on breast cancer treatment. Experience from the preliminary study and close engagement with centres will aid trial success. Funding: OPTIMA is 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, Hughes-Davies L, Makris A, Macpherson IR, Conefrey C, Rooshenas L, Pinder SE, Thomas J, Hall PS, Cameron DA, Earl HM, Naume B, Poole CJ, Rea DW, MacIntosh SA, Harmer V, Morgan A, Hulme C, McCabe C, Stallard N, Higgins H, Donovan JL, Bartlett JM, Marshall A, Dunn JA. OPTIMA: A prospective randomized trial to validate the clinical utility and cost-effectiveness of gene expression test-directed chemotherapy decisions in high clinical risk early breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr OT1-05-02.

Adjuvant trastuzumab for patients with HER2-positive early breast cancer showed significant improvements in both disease-free and overall survival with 12 months of treatment [1,2], which was approved by the National Institute for Health and Care Excellence (NICE) in the UK in 2006. When the FinHer trial showed similar results with 9 weeks of trastuzumab [3], there was significant interest in whether shorter durations might be as effective. Additional benefits for patients could be less toxicity, fewer hospital visits and a more rapid return to normal life, with considerable societal benefits of reduced costs. PERSEPHONE was the pragmatic UK duration trial funded by the National Institute for Health Research, Health Technology Assessment Programme (NIHR HTA), which showed that 6 months of adjuvant trastuzumab was non-inferior to 12 months with a 4-year disease-free survival rate of 89.4% compared with 89.8% (non-inferiority P = 0.01) [4]. Less toxicity was reported with 6 months, particularly cardiac toxicity, and there were cost savings over the first 2 years [5], which were maintained over an average patient's lifetime when extrapolated using an economic model. After the publication of these results in June 2019, the Optimal Duration of Adjuvant Trastuzumab Working Group was convened, comprising a diverse, multidisciplinary membership. There were representatives from the PERSEPHONE Trial Management Group, including patient advocates, the National Cancer Research Institute (NCRI) Breast Group, the Association of Cancer Physicians, the Royal College of Radiologists and the Independent Cancer Patients' Voice. By November 2019, both dual antibody treatment with trastuzumab and pertuzumab [6] and extended neratinib after single-agent trastuzumab [7] had been approved by NICE, only for those at high risk of recurrence. Therefore, single-agent trastuzumab remained standard of care for those at lower risk of recurrence and recommendations were made for these patients.\ud \ud

Background The addition of adjuvant trastuzumab to chemotherapy has significantly improved outcomes in human epidermal growth factor receptor 2 (HER2) positive early, potentially curable breast cancer. Twelve months��� trastuzumab tested in the registration trials was adopted for standard adjuvant treatment in 2006. Subsequently similar outcomes were demonstrated using 9 weeks trastuzumab. Shorter durations were therefore tested for non-inferiority. Objectives To establish whether 6 months��� adjuvant trastuzumab is non-inferior to 12 months in HER2-positive early breast cancer using a primary endpoint of 4-year disease-free-survival (DFS). Design Phase III randomised, controlled, non-inferiority trial. Setting 152 NHS Hospitals. Participants 4088 patients with HER2-positive early breast cancer planned to receive both chemotherapy and trastuzumab. Intervention Randomisation (1:1) between six months��� or twelve months��� trastuzumab. Main outcomes Primary endpoint was DFS four years after diagnosis. Secondary endpoints were overall survival (OS), cost effectiveness, and cardiac function during trastuzumab. Assuming a 4-year DFS rate of 80% with 12 months, 4000 patients were required to demonstrate non-inferiority of 6-months (5% 1-sided significance, 85% power), defining the non-inferiority limit as no worse than 3% below the standard arm. Costs and quality-adjusted life years (QALYs) were estimated by within-trial analysis and a lifetime decision-analytic model. Results Between 4th October 2007 and 31st July 2015, 2045 patients were randomised to 12-months��� trastuzumab and 2043 to 6-months. Sixty-nine percent had ER-positive disease; 90% received anthracyclines (49% with taxanes; 41% without taxanes); 10% received taxanes without anthracyclines; 54% had trastuzumab sequentially after chemotherapy; 85% received adjuvant chemotherapy (58% were node negative). At 6.1 years median follow-up with 389 (10%) deaths, and 566 (14%) DFS events, 4-year DFS rates for the 4088 patients were 89.5% (95% CI, 88.1-90.8) in the 6-month group and 90.3% (95% CI 88.9- 91.5) in the 12-month group (Hazard Ratio 1.10; 90% CI 0.96���1.26, non-inferiority p=0.01), demonstrating non-inferiority of 6-months��� trastuzumab. Congruent results were found for OS (non-inferiority p=0.0003), and landmark analyses 6 months from starting trastuzumab (non-inferiority p=0.03 (DFS) and p=0.006 (OS)). 6-months��� trastuzumab resulted in fewer patients reporting adverse events of severe grade (365/1929 (19%) versus 460/1935 (24%) 12-month patients, p=0.0003) or stopping early because of cardiotoxicity (61/1977 (3%) versus 146/1941 (8%) 12-month patients, p, National Institute for Health Research, Health Technology Assessment Programme (HTA Project: 06/303/98).

Background: Multi-parameter gene expression assays (MPAs) are widely used to estimate individual patient residual risk in hormone-sensitive HER2-negative node-negative early breast cancer, allowing patients with low risk to safely avoid chemotherapy. Evidence for MPA use in node-positive breast cancer is limited. OPTIMA (Optimal Personalised Treatment of early breast cancer usIng Multi-parameter Analysis) aims to validate MPA's as predictors of 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 main eligibility criteria are women or men aged 40 or older with resected ER-positive, HER2-negative breast cancer and up to 9 involved axillary lymph nodes. Randomization is to standard management (chemotherapy and endocrine therapy) or to MPA-directed treatment. Those with a “high risk” tumor MPA score receive standard management whilst those at “low risk” are treated with endocrine therapy alone. The preliminary phase (OPTIMA prelim) evaluated the performance of several MPAs to select a test to be used in the main efficacy trial based on economic analysis, and assessed the feasibility and acceptability of a large UK trial. OPTIMA prelim used Oncotype DX as the primary discriminator; the main trial will use Prosigna (PAM50) with Prosigna Score ≤60 defined as “low-risk”. The co-primary outcomes are (1) Invasive Disease Free Survival (IDFS) and (2) cost-effectiveness of test-directed therapy. Secondary outcomes include IDFS in “low-risk” patients, quality of life and additional survival measures. 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 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 with a 47% acceptance rate. The main study opened in January 2017. Early progress indicates that the recruitment target is achievable in the intended 46-month timescale through the participation of >100 sites Conclusion: OPTIMA, as one of two large scale prospective trials validating the use of test-guided chemotherapy decisions in node-positive early breast cancer, is expected to have a global impact on breast cancer treatment. Experience from OPTIMA prelim showed that patient advocate support and close engagement with sites will aid trial success. Funding: The project is funded in the UK by the 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, Makris A, Hughes-Davies L, Macpherson IR, Hall PS, Cameron DA, Earl HM, Pinder SE, Poole CJ, Rea DW, McIntosh S, Harmer V, Morgan A, Rooshenas L, Conefrey C, Donovan JL, Hulme C, McCabe C, Stallard N, Campbell A, Higgins H, Bartlett JMS, Marshall A, Dunn JA. OPTIMA: A prospective randomized trial to validate the predictive utility and cost-effectiveness of gene expression test-directed chemotherapy decisions in early breast cancer [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 OT1-06-01.

PURPOSE: To establish a comprehensive set of recommendations for the service structure and skill set of nurses and allied healthcare professionals in prostate cancer care. METHODS: Using components of formal consensus methodology, a 30-member multidisciplinary panel produced 53 items for discussion relating to the provision of care for prostate cancer patients by specialist nurses and allied healthcare professionals. Items were developed by two rounds of email correspondence in which, first, items were generated and, second, items refined to form the basis of a consensus meeting which constituted the third round of review. The fourth and final round was an email review of the consensus output. RESULTS: The panel agreed on 33 items that were appropriate for recommendations to be made. These items were grouped under categories of “Environment” and “Patient Pathway” and included comments on training, leadership, communication and quality assessment as well as specific items related to prostate diagnosis clinics, radical treatment clinics and follow-up survivor groups. CONCLUSIONS: Specialist nurses and allied healthcare professionals play a vital role alongside urologists and oncologists to provide care to men with prostate cancer and their families. We present a set of standards and consensus recommendations for the roles and skill-set required for these practitioners to provide gold-standard prostate cancer care. These recommendations could form the basis for development of comprehensive integrated prostate cancer pathways in prostate cancer centres as well as providing guidance for any units treating men with prostate cancer.

Background: Adjuvant trastuzumab significantly improves outcomes for patients with HER2-positive early breast cancer. The standard treatment duration is 12 months but shorter treatment could provide similar efficacy while reducing toxicities and cost. We aimed to investigate whether 6-month adjuvant trastuzumab treatment is non-inferior to the standard 12-month treatment regarding disease-free survival.Methods: This study is an open-label, randomised phase 3 non-inferiority trial. Patients were recruited from 152 centres in the UK. We randomly assigned patients with HER2-positive early breast cancer, aged 18 years or older, and with a clear indication for chemotherapy, by a computerised minimisation process (1:1), to receive either 6-month or 12-month trastuzumab delivered every 3 weeks intravenously (loading dose of 8 mg/kg followed by maintenance doses of 6 mg/kg) or subcutaneously (600 mg), given in combination with chemotherapy (concurrently or sequentially). The primary endpoint was disease-free survival, analysed by intention to treat, with a non-inferiority margin of 3% for 4-year disease-free survival. Safety was analysed in all patients who received trastuzumab. This trial is registered with EudraCT (number 2006–007018–39), ISRCTN (number 52968807), and ClinicalTrials.gov (number NCT00712140).Findings: Between Oct 4, 2007, and July 31, 2015, 2045 patients were assigned to 12-month trastuzumab treatment and 2044 to 6-month treatment (one patient was excluded because they were double randomised). Median follow-up was 5·4 years (IQR 3·6–6·7) for both treatment groups, during which a disease-free survival event occurred in 265 (13%) of 2043 patients in the 6-month group and 247 (12%) of 2045 patients in the 12-month group. 4-year disease-free survival was 89·4% (95% CI 87·9–90·7) in the 6-month group and 89·8% (88·3–91·1) in the 12-month group (hazard ratio 1·07 [90% CI 0·93–1·24], non-inferiority p=0·011), showing non-inferiority of the 6-month treatment. 6-month trastuzumab treatment resulted in fewer patients reporting severe adverse events (373 [19%] of 1939 patients vs 459 [24%] of 1894 patients, p=0·0002) or stopping early because of cardiotoxicity (61 [3%] of 1939 patients vs 146 [8%] of 1894 patients, pInterpretation: We have shown that 6-month trastuzumab treatment is non-inferior to 12-month treatment in patients with HER2-positive early breast cancer, with less cardiotoxicity and fewer severe adverse events. These results support consideration of reduced duration trastuzumab for women at similar risk of recurrence as to those included in the trial.Funding: UK National Institute for Health Research, Health Technology Assessment Programme.

Introduction All published adjuvant chemotherapy trials in breast cancer have made the assumption that the proportional benefits of chemotherapy apply uniformly across molecular subgroups. However, it can be argued that chemotherapy effectiveness for luminal A breast cancer is low in comparison to other subtypes irrespective of tumour stage. A logical extension of this argument is that novel multiparametric tests that use biological features of breast cancers to assess risk may also inform chemotherapy benefit in luminal cancers. The OPTIMA trial is a multi-centre, partially blinded, randomised clinical trial with a non-inferiority endpoint, and an adaptive design, to compare standard treatment (chemotherapy followed by endocrine therapy) with multi-parameter test-guided treatment allocation to either chemotherapy followed by endocrine therapy or endocrine therapy alone. OPTIMA-prelim aimed to compare the predicted risk stratification, sub-type classification and cost effectiveness of different multiparameter tests performed on the same patient population. Methods Over 20 months of recruitment 285 patients were randomised to OPTIMA-prelim. Tissue was collected centrally, ER and HER2 status confirmed and samples provided for testing with Oncotype DX™, Prosigna™ (PAM50), Mammaprint™, Mammatyper™, IHC4-AQUA and IHC4 using conventional biomarkers. Sub-type classification was provided by Blueprint™, Mammatyper™ and Prosigna™. Each test was performed at central diagnostic laboratories (OncotypeDx, Mammaprint/Blueprint, Mammatyper) or in a central laboratory (Prosigna™/IHC4) strictly according to GLP practices. Results Samples from 181 patients randomised by January 2014 were tested and data analysed for this study. Patients were categorised as low/intermediate or high risk using predetermined cut-offs for each test. Oncotype DX predicted a proportion of low-risk tumours (79%; 95% CI 73-85%) similar to that predicted as either low or intermediate risk using Prosigna ROR_P (71%; 95% CI 64-78%) and IHC4 (69%; 95% CI 62-76%), whilst MammaPrint identified the fewest low-risk tumours (59%; 95% CI 52-66%). Strikingly, a comparison between tests showed modest agreement between tests when dichotomising results between high vs low/intermediate risk. Disagreement between different tests, in assigning individual tumours to risk categories, is not uncommon; for the four tests [Oncotype DX, MammaPrint, Prosigna ROR_P (low/int) and IHC4 (low/int)], only 71 (39%) tumours were classified as low/intermediate risk for all four tests and only 17 (9%) tumours were high risk for all four tests, 93 (52%) tumours were assigned to different risk categories by different tests. Similarly all three subtypes tests (Blueprint/Prosigna/Mammatyper) each assigned 59% of tumors to luminal A subtype but only 70% of these cases were classified as luminal A by all three assays. Conclusion Existing evidence on the comparative prognostic information provided by different tests suggests current multiparameter tests provide broadly equivalent risk information for the population of women with luminal breast cancers. However, for the individual patient, tests may provide differing risk categorisation or indeed subtype information. Acknowledgement This project was funded by the NIHR Health Technology Assessment (HTA) Programme (project 10/34/01). The opinions expressed therein are those of the authors and do not necessarily reflect those of the HTA programme, NIHR, NHS or Department of Health. Citation Format: John MS Bartlett, Robert C Stein, Jane Bayani, Andrea Marshall, Janet A Dunn, Amy F Campbell, Carrie Cunningham, Monika Sobol, Peter Hall, Leila Rooshenas, Adrienne Morgan, Christopher Poole, Sarah E Pinder, David A Cameron, Nigel Stallard, Jenny Donovan, Christopher McCabe, Luke Hughes-Davies, Andreas Makris, on Behalf of the OPTIMA Trial Management Group. Comparison of multiparameter tests in the UK OPTIMA-Prelim trial [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-11-07.

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™. Additional testing was undertaken using alternative tests: MammaPrint TM , PAM-50 (Prosigna TM ), MammaTyper TM , IHC4, and IHC4-AQUA™ (NexCourse Breast™). 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.

Background: No specific targeted therapies are available for Triple Negative Breast Cancers (TNBC), an aggressive and diverse subgroup. The basal TNBC subgroup show some phenotypic and molecular similarities with germline BRCA (gBRCA). In gBRCA patients, and potentially other homologous recombination deficiencies, these already compromised pathways may allow drugs called PARP inhibitors (olaparib) to work more effectively. Aims: To establish if the addition of olaparib to neoadjuvant platinum based chemotherapy for basal TNBC and/or gBRCA breast cancer is safe and improves efficacy (pathological complete response (pCR)). Trial design: 3 stage open label randomised phase II/III trial of neoadjuvant paclitaxel and carboplatin +/olaparib, followed by clinicians' choice of anthracycline regimen. Stage 1 and 2: Patients are randomised (1:1:1) to either control (3 weekly carboplatin AUC5/weekly paclitaxel 80mg/m2 for 4 cycles) or one of two research arms with the same chemotherapy regimen but with two different schedules of olaparib 150mg BD for 12 days. Stage 3: Patients are randomised (1:1) to either control arm or to the research arm selected in stage 2. Methods: Stage 1 Safety: both research arms combined. Stage 2 Schedule selection criteria: pCR rate and completion rate of olaparib protocol treatment. It is a “pickthewinner” design with 53 patients in each research arm. This allows a 90% power, 5% onesided significance level to test null hypothesis of pCR ≤35% versus an alternative hypothesis of pCR ≥55% in each of the research arms. Stage 3 Efficacy:anticipated pCR ˜55-60% for all trial patients and ˜60-65% for gBRCA patients. The trial is powered to detect an absolute improvement of 15% (all patients) and 20% (gBRCA patients) by adding olaparib to chemotherapy (enriched design). TNBC patient recruitment will be capped, to ensure required gBRCA patients are enrolled. Enrichment design is applied with overall significance level 0.05(α) = 0.025(αall)+ 0.025(αgBRCA) and 80% power. Target accrual: 527 [gBRCA 220] Current accrual: 56 Sites activated: 15 [expected number of sites 30-50]. Citation Format: Abraham J, Vallier A-L, Qian W, Grybowicz L, Thomas S, Machin A, Harvey C, Chiu E, McAdam K, Hughes-Davies L, Roylance R, Copson E, Armstrong A, Provenzano E, Tischkowitz M, McMurtry E, Earl H. PARTNER randomised, phase II/III trial to evaluate the safety and efficacy of the addition of olaparib to platinum based neoadjuvant chemotherapy in triple negative and/or germline BRCA mutated breast cancer patients [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 OT3-04-03.

Background: No specific targeted therapies are available for Triple Negative Breast Cancers (TNBC), an aggressive and diverse subgroup. The basal TNBC sub-group share some phenotypic and molecular similarities with germline BRCA (gBRCA) tumours. In gBRCA patients, and potentially other homologous recombination deficiencies, these already compromised pathways may allow drugs called PARP inhibitors (Olaparib) to work more effectively. Aims: To establish if the addition of olaparib to neoadjuvant platinum based chemotherapy for basal TNBC and/or gBRCA breast cancer is safe and improves efficacy (pathological complete response (pCR)). Methods: Trial design: 3-stage open label randomised phase II/III trial of neoadjuvant paclitaxel and carboplatin +/- olaparib, followed by clinicians' choice of anthracycline regimen. Stage 1 and 2: Randomisation (1:1:1) to either control (3 weekly carboplatin AUC5/weekly paclitaxel 80mg/m2 for 4 cycles) or one of two research arms with the same chemotherapy regimen but with two different schedules of olaparib 150mg BD for 12 days. Stage 3: Patients are randomised (1:1) to either control arm or to the research arm selected in stage 2. End-points: Stage 1: Safety; Stage 2: Schedule selection using pCR rate and completion rate of olaparib using a “pick-the-winner” design. Stage 3: pCR rate. Enrichment design is applied with an overall significance level 0.05(α) and 80% power. A total of 527 patients will be included to detect an absolute improvement of 15% (all patients) and 20% (gBRCA patients) by adding olaparib to platinum based chemotherapy. Trial Progress: PARTNER has been recruiting in UK since 27th May 2016. IDSMC recommended to continue the trial without change after reviewing the Stage 1 safety data. The recruitment of stage 2 was completed in April 2018 and results to be reviewed by the IDSMC in early 2019. The trial is open and enrolling patients to national and international sites. Citation Format: Abraham J, Vallier A-L, Qian W, Machin A, Grybowicz L, Thomas S, Weiss M, Harvey C, McAdam K, Hughes-Davies L, Roberts A, Roylance R, Copson E, Pinilla K, Armstrong A, Provenzano E, Tischkowitz M, McMurty E, Earl H. PARTNER: Randomised, phase II/III trial to evaluate the safety and efficacy of the addition of olaparib to platinum-based neoadjuvant chemotherapy in triple negative and/or germline BRCA mutated breast cancer patients [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr OT3-03-03.

Background: In patients with TNBC, following standard neoadjuvant chemotherapy, residual disease (RD) is correlated with poor prognosis and 50% relapse within 5 years [1]. PARTNER is a neoadjuvant clinical trial which randomises TNBC and gBRCAm patients to carboplatin and paclitaxel +/- olaparib followed by anthracycline-based chemotherapy. Patients with RD after neoadjuvant treatment in this trial also face poorer survival outcomes, due to the paucity of treatment options. PARTNERING, develops a new strategy using novel agent combinations as an alternative pathway for patients with RD within the PARTNER trial. Methods: PARTNERING is a phase II open label, sub-study with a two-stage Simon design with biomarker guided treatment cohorts open only to patients in the PARTNER trial. A maximum of 15 patients will be included in each cohort. Patients with RD > 10% tumour cellularity (TC) on biopsy after neoadjuvant therapy will be eligible. Patients who have no tumour cells or < 10% TC, and those with progressive disease will be excluded. Allocation of patients into the cohorts will be based on tumour infiltrating lymphocytes (TILs) expression either on diagnostic or post treatment biopsy. Patients with tumours with TILs score ≤20% are considered “non-immunogenic” They will be stratified according to HRD status and allocated to receive a cell cycle checkpoint inhibitor + olaparib. Patients with a TILs score >20% are considered “immunogenic” and will be allocated to receive an immune checkpoint inhibitor with olaparib or a cell cycle checkpoint inhibitor. Primary outcome measure is pCR / MRD rate at surgery after the administration of 2 cycles / 8 weeks of a combination of new agents. The rate of conversion to pCR/MRD will be correlated with TC, TILs, BRCA and homologous recombination deficiency (HRD) status, Ki67% and previous olaparib treatment. Progress: The PARTNERING pathway in the PARTNER trial will be open late 2018. Citation Format: Abraham JE, Vallier A-L, Qian W, Machin A, Grybowicz L, Thomas S, Weiss M, Harvey C, McAdam K, Hughes-Davies L, Roberts A, Provenzano E, Pinilla K, Roylance R, Copson E, Armstrong A, McMurtry E, Tischkowitz M, Earl HM. PARTNERING / PARTNER : Phase II sub-study to establish if the addition of combinations of new agents (olaparib, cell cycle and immune checkpoint inhibitors) can improve the rate of pathological complete response (pCR) and minimal residual disease (MRD) in triple negative breast cancer (TNBC) and / or germline BRCA mutated (gBRCAm) patients with evidence of residual disease after PARTNER therapy [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr OT3-01-02.

The ARTemis Trial tested standard neoadjuvant chemotherapy±bevacizumab in the treatment of HER2-negative early breast cancer. We compare data from central pathology review with report review and also the reporting behavior of the two central pathologists. Eight hundred women with HER2-negative early invasive breast cancer were recruited. Response to chemotherapy was assessed from local pathology reports for pathological complete response in breast and axillary lymph nodes. Sections from the original core biopsy and surgical excision were centrally reviewed by one of two trial pathologists blinded to the local pathology reports. Pathologists recorded response to chemotherapy descriptively and also calculated residual cancer burden. 10% of cases were double-reported to compare the central pathologists’ reporting behavior. Full sample retrieval was obtained for 681 of the 781 patients (87%) who underwent surgery within the trial and were evaluable for pathological complete response. Four hundred and eighty-three (71%) were assessed by JSJT, and 198 (29%) were assessed by EP. Residual cancer burden calculations were possible in 587/681 (86%) of the centrally reviewed patients, as 94/681 (14%) had positive sentinel nodes removed before neoadjuvant chemotherapy invalidating residual cancer burden scoring. Good concordance was found between the two pathologists for residual cancer burden classes within the 65-patient quality assurance exercise (kappa 0.63 (95% CI: 0.57–0.69)). Similar results were obtained for the between-treatment arm comparison both from the report review and the central pathology review. For pathological complete response, report review was as good as central pathology review but for minimal residual disease, report review overestimated the extent of residual disease. In the ARTemis Trial central pathology review added little in the determination of pathological complete response but had a role in evaluating low levels of residual disease. Calculation of residual cancer burden was a simple and reproducible method of quantifying response to neoadjuvant chemotherapy as demonstrated by performance comparison of the two pathologists.

The BRCA2 gene is mutated in familial breast and ovarian cancer, and its product is implicated in DNA repair and transcriptional regulation. Here we identify a protein, EMSY, which binds BRCA2 within a region (exon 3) deleted in cancer. EMSY is capable of silencing the activation potential of BRCA2 exon 3, associates with chromatin regulators HP1β and BS69, and localizes to sites of repair following DNA damage. EMSY maps to chromosome 11q13.5, a region known to be involved in breast and ovarian cancer. We show that the EMSY gene is amplified almost exclusively in sporadic breast cancer (13%) and higher-grade ovarian cancer (17%). In addition, EMSY amplification is associated with worse survival, particularly in node-negative breast cancer, suggesting that it may be of prognostic value. The remarkable clinical overlap between sporadic EMSY amplification and familial BRCA2 deletion implicates a BRCA2 pathway in sporadic breast and ovarian cancer.

Despite the perception of many oncologists that tamoxifen is an inferior drug, and should be substituted by an aromatase inhibitor in post-menopausal women, the current evidence strongly supports the view that AIs should be used 2-3 years after tamoxifen to achieve the maximal overall survival (OS) advantage.

Nuclear factor-kappaB pathway (NF-kappaB) is activated in many breast cancers. NF-small kappaB has interactions with other pathways such as the nerve growth factor (NGF) pathway, which is involved in the survival and proliferation of breast cancer cells. NGF treatment of breast cancer cells activates NF-kappaB resulting in the inhibition of ceramide-induced apoptosis. NGF effects on apoptosis and cell proliferation are mediated through p75NTR and p140TrkA receptors, respectively. In this study we investigate the NGF/NF-kappaB pathway as a therapeutic target in breast cancer.We demonstrate that p75NTR inhibitor Pep5, p140TrkA inhibitor K-252a, and NF-kappaB inhibitor BAY11-7085 have pro-apoptotic and anti-proliferation activities in breast cancer cells. We also show a synergy in combining the NGF receptor inhibitors with the conventional breast cancer treatments tamoxifen and taxol.These data suggest that NGF/NF-kappaB pathway is a potential therapeutic target in breast cancer.

Background: The ARTemis trial was developed to assess the efficacy and safety of adding bevacizumab to standard neoadjuvant chemotherapy in HER2-negative early breast cancer.Methods: In this randomised, open-label, phase 3 trial, we enrolled women (≥18 years) with newly diagnosed HER2-negative early invasive breast cancer (radiological tumour size >20 mm, with or without axillary involvement), at 66 centres in the UK. Patients were randomly assigned via a central computerised minimisation procedure to three cycles of docetaxel (100 mg/m2 once every 21 days) followed by three cycles of fluorouracil (500 mg/m2), epirubicin (100 mg/m2), and cyclophosphamide (500 mg/m2) once every 21 days (D-FEC), without or with four cycles of bevacizumab (15 mg/kg) (Bev+D-FEC). The primary endpoint was pathological complete response, defined as the absence of invasive disease in the breast and axillary lymph nodes, analysed by intention to treat. The trial has completed and follow-up is ongoing. This trial is registered with EudraCT (2008-002322-11), ISRCTN (68502941), and ClinicalTrials.gov (NCT01093235).Findings: Between May 7, 2009, and Jan 9, 2013, we randomly allocated 800 participants to D-FEC (n=401) and Bev+D-FEC (n=399). 781 patients were available for the primary endpoint analysis. Significantly more patients in the bevacizumab group achieved a pathological complete response compared with those treated with chemotherapy alone: 87 (22%, 95% CI 18–27) of 388 patients in the Bev+D-FEC group compared with 66 (17%, 13–21) of 393 patients in the D-FEC group (p=0·03). Grade 3 and 4 toxicities were reported at expected levels in both groups, although more patients had grade 4 neutropenia in the Bev+D-FEC group than in the D-FEC group (85 [22%] vs 68 [17%]).Interpretation: Addition of four cycles of bevacizumab to D-FEC in HER2-negative early breast cancer significantly improved pathological complete response. However, whether the improvement in pathological complete response will lead to improved disease-free and overall survival outcomes is unknown and will be reported after longer follow-up. Meta-analysis of available neoadjuvant trials is likely to be the only way to define subgroups of early breast cancer that would have clinically significant long-term benefit from bevacizumab treatment.Funding: Cancer Research UK, Roche, Sanofi-Aventis.

TPS623Background: Multi-parameter gene expression assays (MPAs) are widely used to estimate individual patient residual risk and guide chemotherapy use in hormone sensitive HER2-ve early breast cancer, but prospective validation data are not available. 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 RCT with an adaptive two-stage design. The preliminary phase (OPTIMA prelim) evaluated the performance of MPAs to identify a suitable test to be used in the main efficacy trial, and demonstrated the feasibility and acceptability of a large UK trial. Eligible patients (pts) are men or women aged ≥ 40 years who have surgically resected early stage ER+ve and HER2-ve breast cancer, and have either 1-9 involved axillary lymph nodes or tumors of ≥ 30mm diameter. Randomization is to standard management (chemotherapy followed by endocrine therapy) or to MPA-directed thera...

TPS591 Background: No specific targeted therapies are available for Triple Negative Breast Cancers (TNBC), an aggressive and diverse subgroup. The basal TNBC sub-group show some phenotypic and molecular similarities with germline BRCA (gBRCA). In gBRCA patients, and potentially other homologous recombination deficiencies, these already compromised pathways may allow drugs called PARP inhibitors (olaparib) to work more effectively. Aims: To establish if the addition of olaparib to neoadjuvant platinum based chemotherapy for basal TNBC and/or gBRCA breast cancer is safe and improves efficacy (pathological complete response (pCR)). Trial design: 3-stage open label randomised phase II/III trial of neoadjuvant paclitaxel and carboplatin +/- olaparib, followed by clinicians' choice of anthracycline regimen. Stage 1 and 2: Patients are randomised (1:1:1) to either control (3 weekly carboplatin AUC5/weekly paclitaxel 80mg/m2 for 4 cycles) or one of two research arms with the same chemotherapy regimen but with two different schedules of olaparib 150mg BD for 12 days. Stage 3: Patients are randomised (1:1) to either control arm or to the research arm selected in stage 2. Methods: Stage 1 - Safety: both research arms combined. Stage 2 - Schedule selection criteria: pCR rate and completion rate of olaparib protocol treatment. It is a “pick-the-winner” design with 53 patients in each research arm. This allows a 90% power, 5% one-sided significance level to test null hypothesis of pCR ≤35% versus an alternative hypothesis of pCR ≥55% in each of the research arms. Stage 3 - Efficacy: anticipated pCR ~55-60% for all trial patients and ~60-65% for gBRCA patients. The trial is powered to detect an absolute improvement of 15% (all patients) and 20% (gBRCA patients) by adding olaparib to chemotherapy (enriched design). TNBC patient recruitment will be capped, to ensure required gBRCA patients are enrolled. Enrichment design is applied with overall significance level 0.05(α) = 0.025(αall)+ 0.025(αgBRCA) and 80% power. Target accrual: 527 [gBRCA 220] Current accrual: 17 Sites activated: 12 [expected number of sites 30-50].

Background: Triple Negative Breast Cancers (TNBC) are a biologically diverse and aggressive sub-group. Early effective treatment can lead to cure. Current standard treatment is systemic chemotherapy either pre-/post-definitive surgery. No specific targeted therapies are available for TNBC. There are phenotypic and molecular similarities between germline BRCA (gBRCA) breast cancer and TNBC. In TNBC 10%-20% harbour gBRCA mutations. In gBRCA patients, and potentially other homologous recombination deficiencies, these already compromised pathways allow drugs called PARP inhibitors (olaparib) to work particularly effectively. Aims: To establish if the addition of olaparib to neoadjuvant platinum-based chemotherapy for TNBC and/or gBRCA breast cancer is safe and improves efficacy. Trial design: 3-stage open label randomised phase II/III trial of neoadjuvant olaparib +/- platinum containing chemotherapy followed by clinicians' choice of anthracycline regimen. Stage 1 and 2, patients are randomised (1:1:1) to either control (3 weekly carboplatin AUC5/weekly paclitaxel 80mg/m2 chemotherapy - 4 cycles) or one of two research arms which uses the same chemotherapy regimen but with two different schedules of olaparib 150mg BD). Stage 3: patients are randomised (1:1) to either control arm or to the research arm selected in stage 2. Primary outcome measures: Stage 1: safety of the addition of olaparib to chemotherapy. Prophylactic G-CSF is mandatory. Stage 2: pathological complete response (pCR) in each of the two research arms. At the end of stage 2, one of the research arms will be dropped. Stage 3: pCR at surgery after neoadjuvant treatment. pCR - defined as no residual invasive carcinoma within the breast (ductal carcinoma in situ permitted) AND no evidence of metastatic disease within the lymph nodes. Eligibility: •Aged 16 to 70. •Written informed consent. •Histologically confirmed invasive breast cancer. •Clinical stage T1-4 N0-2 (tumour or metastatic node diameter>10mm) •Confirmed ER-negative and HER2-negative or gBRCA mutation positive, irrespective of hormone status. •Performance Status 0-1 Statistical Methods: Stage 1, Safety: both research arms combined. Stage 2, Schedule selection criteria: pCR rate and completion rate of olaparib protocol treatment. It is a “pick-the winner” design with 53 patients in each research arm. This allows a 90% power, 5% one-sided significance level to test null hypothesis of pCR ≤35% versus an alternative hypothesis of pCR ≥55% in each of the research arms. Stage 3, Efficacy: anticipated pCR ∼45-55% for all trial patients and ∼50-60% for gBRCA patients. The trial is powered to detect an absolute improvement of 15% (all patients) and 20% (gBRCA patients) by adding olaparib to chemotherapy (enriched design). TNBC patient recruitment will be capped, to ensure the required number of gBRCA patients are enrolled. Enrichment design is applied with the overall significance level 0.05(α)=0.025(αall)+ 0.025(αgBRCA) and 80% power. Present accrual: 1 [Trial opened: 23rd May 2016] Target accrual: 527 (TNBC 307; gBRCA 220) Contact information: Dr. Jean Abraham; Email: ja344@medschl.cam.ac.uk. Citation Format: Abraham JE, Vallier A-L, Qian W, Grybowicz L, Thomas S, Mahmud S, Harvey C, McAdam K, Hughes-Davies L, Roylance R, Copson E, Brown J, Provenzano E, Tischkowitz M, Earl HM. PARTNER - Randomised, phase II/III trial to evaluate the safety and efficacy of the addition of olaparib to platinum-based neoadjuvant chemotherapy in triple negative and/or germline BRCA mutated breast cancer patients [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 OT2-01-15.

1014Background: ARTemis compared the addition of Bev to neoadjuvant D-FEC in HER2 negative breast cancer. Improved pathological complete response (pCR) with Bev has been reported previously. Method...

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.\ud \ud 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.\ud \ud 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.\ud \ud 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: 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.

The mortality from breast cancer has improved steadily over the past two decades, in part because of the increased use of more effective adjuvant therapies. Thousands of women are routinely treated with intensive chemotherapy, which can be unpleasant, is expensive and is occasionally hazardous. Oncologists have long known that some of these women may not need treatment, either because they have a low risk of relapse or because they have tumour biology that makes them less sensitive to chemotherapy and more suitable for early adjuvant endocrine therapy. There is an urgent need to improve patient selection so that chemotherapy is restricted to those patients who will benefit from it. Here we review the emerging technologies that are available for improving patient selection for chemotherapy. We describe the OPTIMA trial, which has just opened to recruitment in the UK, is the latest addition to trials in this area, and is the first to focus on the relative cost-effectiveness of alternate predictive assays.

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.

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...

Purpose: To examine the presentation, management, and outcome of patients with extensive intrathoracic involvement in early-stage Hodgkin's disease. Patients and Methods: One hundred seventy-two patients with clinical Stage IA-IIB Hodgkin's disease and extensive intrathoracic involvement were studied. Extensive intrathoracic disease was defined as either large mediastinal adenopathy (LMA, defined as the width of the mass greater than one-third the maximum thoracic diameter, n = 154) or as extensive (>10 cm) cephalocaudad intrathoracic disease that did not fulfill formal chest radiograph criteria for LMA (n = 18). Patients were divided into three groups based on staging and extent of treatment. Forty-seven patients were treated with radiation alone after a laparotomy (RT-lap), 47 patients received combined modality therapy after laparotomy (CMT-lap), and 78 patients were treated with combined modality therapy without staging laparotomy ( CMT-no lap). MOPP was used in 82% of the CMT patients. Low-dose whole-cardiac RT was used in nearly 50% of patients treated either with RT or CMT. Results: The 10-year actuarial freedom from relapse rates were 54% with RT alone and 88% with CMT (p = 0.001); overall survival rates were 84 and 89%, respectively (p = NS). The median time to relapse was only 17 months. Over 80% of relapses occurred within the first 3 years. The most common site of relapse in all patients was the mediastinum. Relapses below the diaphragm were rare, even in CMT patients who did not receive abdominal radiation treatment. The principal acute morbidity was symptomatic pneumonitis, which occurred in 29% of patients receiving any part of their chemotherapy after RT, compared to 13% if all the chemotherapy was given before RT and 11% if RT alone was administered. There was a low late risk of myocardial infarction (3%) in the two groups with the longest follow up (RT-lap, CMT-lap), but a higher risk of second malignancy in the CMT-lap group (21%) compared with the RT-lap group (2%). Conclusion: Extensive intrathoracic involvement is a distinctive presentation of early-stage HD that has a high relapse risk if treated with RT alone. The introduction of CMT has been associated with improvements in freedom from relapse. The low rate of peripheral relapse with CMT suggests that reductions in field size may be achievable. The use of low-dose whole-heart RT with modern techniques is not associated with a high risk of late cardiac complications and should be used in patients who present with extensive pericardial disease or cardiophrenic lymphadenopathy. The high rate of second malignancy in the CMT group with the longest follow-up suggests that careful long-term surveillance for such patients is warranted.

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

TPS665 Background: “Multi-parameter” prognostic tests such as Oncotype DX are increasingly used to identify women with ER +ve HER2 -ve breast cancer treated with endocrine therapy who are unlikely to benefit meaningfully from adjuvant chemotherapy. The supporting evidence for predictive testing is retrospective and is strongest for women with negative nodes. Randomised trials to validate testing are in progress but more evidence is needed, especially for node positive disease. There is early evidence that other multi-parameter tests which are in development have a predictive utility. Methods: OPTIMA will assess the value of multi-parameter tests in a UK population. OPTIMA prelim, the feasibility phase, will recruit 300 patients from May 2012 (with a 200 patient bridging extension to the main study). Eligible patients will have ER +ve HER2 -ve tumours with involved nodes (pN1-2). Patients will be randomised to the standard arm of both chemotherapy and endocrine therapy, or to the “test-directed treatment” arm in which patients will be assigned either the same chemotherapy and endocrine therapy or endocrine therapy only according to the result of an Oncotype DX test. OPTIMA prelim has 3 objectives. (1) To establish whether randomisation to test-directed treatment is acceptable to patients and clinicians. This will be done through qualitative research with in-depth interviews with OPTIMA researchers and by recording and analysing consultations when the trial is discussed with potential participants. (2) Alternative multi-parameter tests will be evaluated on all patients’ tumours and their performance will be compared to Oncotype DX using statistical and cost-effectiveness analysis to select a candidate test(s) appropriate for NHS use to be evaluated in the main trial. (3) The success of the main trial depends on efficient tumour sample collection and analysis to avoid treatment delays. The obstacles to this will be analysed in detail using a sample tracking database. The main study is an efficacy trial of 2-3 arms with the same design but uses tests selected in OPTIMA prelim. It will compare 5-year relapse free survival of test-directed vs. conventional treatment with a non-inferiority hypothesis.

This report describes the radiosurgical treatment of a high neck lesion in a patient with familial multifocal bilateral chemodactoma. The necessary modifications to standard radiosurgery are described. The advantages of this treatment modality for patients with familial chemodactoma are discussed.

Background We have previously demonstrated that BEX2 is differentially expressed in breast tumors and has a significant role in promoting cell survival and growth in breast cancer cells. BEX2 expression protects breast cancer cells against mitochondrial apoptosis and G1 cell cycle arrest. In this study we investigated the transcriptional regulation of BEX2 and feedback mechanisms mediating the cellular function of this gene in breast cancer. Results We found a marked induction of BEX2 promoter by c-Jun and p65/RelA using luciferase reporter assays in MCF-7 cells. Furthermore, we confirmed the binding of c-Jun and p65/RelA to the BEX2 promoter using a chromatin immunoprecipitation assay. Importantly, transfections of c-Jun or p65/RelA in MCF-7 cells markedly increased the expression of BEX2 protein. Overall, these results demonstrate that BEX2 is a target gene for c-Jun and p65/RelA in breast cancer. These findings were further supported by the presence of a strong correlation between BEX2 and c-Jun expression levels in primary breast tumors. Next we demonstrated that BEX2 has a feedback mechanism with c-Jun and p65/RelA in breast cancer. In this process BEX2 expression is required for the normal phosphorylation of p65 and IκBα, and the activation of p65. Moreover, it is necessary for the phosphorylation of c-Jun and JNK kinase activity in breast cancer cells. Furthermore, using c-Jun stable lines we showed that BEX2 expression is required for c-Jun mediated induction of cyclin D1 and cell proliferation. Importantly, BEX2 down-regulation resulted in a significant increase in PP2A activity in c-Jun stable lines providing a possible underlying mechanism for the regulatory effects of BEX2 on c-Jun and JNK. Conclusions This study shows that BEX2 has a functional interplay with c-Jun and p65/RelA in breast cancer. In this process BEX2 is a target gene for c-Jun and p65/RelA and in turn regulates the phosphorylation/activity of these proteins. These suggest that BEX2 is involved in a novel feedback mechanism with significant implications for the biology of breast cancer.