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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: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.

It is well established that cancer and its treatment, whether by chemotherapy, radiotherapy, hormone therapy, or surgery, can adversely impact reproductive function in both women and men. The effects of cancer treatment on reproductive function in both sexes may lead to loss of fertility, sexual desire and function, and hormone deficiency, which results in additional long-term morbidity in more than a third of patients. Given the importance of reproductive function to most people, and the often devastating effect of cancer treatment on it, we propose that proactive assessment of the functional and endocrinological impact of treatment be made a vital component of the assessment of modern cancer treatment, and should be a routine part of discussions with patients before and after treatment, both in trials and in routine care. Reproductive counselling should be proactive and encouraged, as implementation of such counselling has been shown to be beneficial to patient mental health, quality of life, and adherence to treatment. Similarly, efforts should be made to provide more adequate and accurate information to patients, as well as to offer appropriate fertility preservation approaches, which may potentially influence their treatment decisions., SCOPUS: ar.j, info:eu-repo/semantics/published

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.

TPS599 Background: Multi-parameter tumor gene expression assays (MPAs) are validated tools to assist adjuvant chemotherapy decisions for post-menopausal women with luminal-type node-negative breast cancer. Currently there is less certainty for women with 1-3 involved axillary lymph nodes and no information on MPA use for patients with higher level nodal involvement. Three RCTs with available data report chemotherapy benefit for premenopausal women; with limited use of ovarian function suppression (OFS) for non-chemotherapy treated participants, chemotherapy-induced menopause may explain these results. Methods: OPTIMA is an international academic, partially-blinded RCT of test-directed chemotherapy treatment with an adaptive design. Women and men aged 40 or older with resected luminal-type breast cancer may participate if they fulfil one of the following stage criteria: pN1-2; pN1mi with pT ≥20mm; pN0 with pT ≥30mm. Consenting patients are randomized between standard treatment with chemotherapy followed by endocrine therapy or to undergo Prosigna testing; those with high-Prosigna Score ( > 60) tumors receive standard treatment whilst those with low-score tumors are treated with endocrine therapy alone. Patients are informed only of their treatment; test details, and randomization for chemotherapy-treated patients are masked. Clinical choice of chemotherapy is declared at randomization from a menu of standard regimens. Endocrine therapy must be for at least 5 years. Women postmenopausal at trial entry should receive an AI; men, tamoxifen; and premenopausal women, either an AI or tamoxifen, and OFS for 3 or more years; OFS initiation may be deferred because of post-chemotherapy amenorrhea. OPTIMA aims to randomize 2250 patients in each arm to demonstrate non-inferiority of test directed treatment, defined as not more than 3% below the estimated 85% 5-year IDFS for the control arm with a one sided 5% significance level. Power is 81% assuming recruitment over 96-months from January 2017 and 12 months minimum follow-up. OPTIMA also has at least 80% power to demonstrate 3.5% non-inferiority of IDFS for patients with low Prosigna Score tumors (estimated 65% of participants). Cox proportional hazards models will be used to explore important prognostic factors including menopausal status. Additional secondary endpoints include DRFI. A cost-effectiveness analysis of protocol specified MPA driven treatment against standard clinical practice will be conducted. At 31/01/2021, 2004 patients had been randomized. The DMC reviewed the trial in December 2020 with knowledge of related trial results and suggested that the trial continues as planned. OPTIMA is registered as ISRCTN42400492 and funded by the UK NIHR Health Technology Assessment Programme, award number 10/34/501. Clinical trial information: ISRCTN42400492.

Introduction Women who have been treated for breast cancer identify vasomotor symptoms, such as hot flushes and night sweats (HFNS), as a serious problem. An estimated 550 000 people live in the UK today with a diagnosis of breast cancer and up to 70% experience HFNS. Estrogen replacement remains the most effective treatment for hot flushes. However, this is contraindicated in the majority of women with estrogen‐dependent breast cancer. Fewer than 50% of women with estrogen receptor (ER) ‐positive breast cancer complete the recommended 5 years of endocrine treatment—tamoxifen and aromatase inhibitors (AIs). This lack of adherence leads to a 20% excess breast cancer mortality. This lack of adherence may be due to unacceptable side effects such as HFNS. Objectives Patient members of the National Cancer Research Institute UK Breast Clinical Studies Group identified that there is very little research into the management of symptoms after breast cancer treatment. In response we established a Working Party on Symptom Management. The members all have a particular interest in the management of HFNS, and include patients, as well as clinical and academic partners representing oncology, psychology, gynaecology, complementary therapies and the voluntary sector. Methods We gauged current clinical practice of the management of HFNS by surveying breast cancer patients, general practitioners (GPs) and healthcare professionals (HCPs) and we will present these data. Results Forty percent of patients reported that no HCPs or GPs had asked them about HFNS. Despite >90% of GPs and HCPs reporting that they prescribed drugs to alleviate HFNS, only 26% of the patients had been offered drugs and fewer than 2% said they helped; 31% of the patients said that the HFNS were severe enough for them to consider stopping endocrine therapy. Conclusion If women are to be helped to adhere to their life‐saving treatment, new approaches need to be developed to ameliorate HFNS.

Objective To evaluate the impact of the QuinteT Recruitment Intervention (QRI) on recruitment in challenging randomized controlled trials (RCTs) that have applied the intervention. The QRI aims to understand recruitment difficulties and then implements “QRI actions” to address these as recruitment proceeds. Study Design and Setting A mixed-methods study, comprising (1) before-and-after comparisons of recruitment rates and the numbers of patients approached and (2) qualitative case studies, including documentary analysis and interviews with RCT investigators. Results Five UK-based publicly funded RCTs were included in the evaluation. All recruited to target. Randomized controlled trial 2 and RCT 5 both received up-front prerecruitment training before the intervention was applied. Randomized controlled trial 2 did not encounter recruitment issues and recruited above target from its outset. Recruitment difficulties, particularly communication issues, were identified and addressed through QRI actions in RCTs 1, 3, 4, and 5. Randomization rates significantly improved after QRI action in RCTs 1, 3, and 4. Quintet Recruitment Intervention actions addressed issues with approaching eligible patients in RCTs 3 and 5, which both saw significant increases in the number of patients approached. Trial investigators reported that the QRI had unearthed issues they had been unaware of and reportedly changed their practices after QRI action. Conclusion There is promising evidence to suggest that the QRI can support recruitment to difficult RCTs. This needs to be substantiated with future controlled evaluations.

Jo Brett,1 Mary Boulton,1 Debbie Fenlon,2 Nick J Hulbert-Williams,3 Fiona M Walter,4 Peter Donnelly,5 Bernadette A Lavery,6 Adrienne Morgan,7 Carolyn Morris,7 Eila K Watson1 1Faculty of Health and Life Sciences, Oxford Brookes University, Oxford, 2College of Human and Health Sciences, Swansea University, Swansea, Wales, 3Department of Psychology, Chester Research Unit for the Psychology of Health, University of Chester, Chester, 4Department of Public Health and Primary Care, University of Cambridge, Cambridge, 5South Devon Healthcare NHS Foundation Trust, Torbay Hospital, Torquay, 6Cancer Services, Oxford University Hospitals Foundation NHS Trust, Oxford, 7Independent Cancer Patients’ Voice, London, UK Introduction: Despite evidence of the efficacy of adjuvant endocrine therapy (AET) in reducing the risk of recurrence and mortality after treatment for primary breast cancer, adherence to AET is suboptimal. This study aimed to explore factors that influence adherence and nonadherence to AET following breast cancer to inform the development of supportive interventions.Methods: Interviews were conducted with 32 women who had been prescribed AET, 2–4years following their diagnosis of breast cancer. Both adherers (n=19) and nonadherers (n=13) were recruited. The analysis was conducted using the Framework approach.Results: Factors associated with adherence were as follows: managing side effects including information and advice on side effects and taking control of side effects, supportive relationships, and personal influences. Factors associated with nonadherence were as follows: burden of side effects, feeling unsupported, concerns about long-term AET use, regaining normality, including valuing the quality of life over length of life, and risk perception.Conclusion: Provision of timely information to prepare women for the potential side effects of AET and education on medication management strategies are needed, including provision of timely and accurate information on the efficacy of AET in reducing breast cancer recurrence and on potential side effects and ways to manage these should they arise. Trust in the doctor–patient relationship and clear patient pathways for bothersome side effects and concerns with AET are important. Training and education on AET for GPs should be considered alongside novel care pathways such as primary care nurse cancer care review and community pharmacist follow-up. Keywords: hormone therapy, oncology, patient experiences, support, follow-up

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.

This study evaluated the Beliefs about Medicine Questionnaire to explore adherence to adjuvant endocrine therapy after treatment for breast cancer (BMQ-AET). Factor structure of the BMQ-AET was explored alongside internal consistency, convergent validity and acceptability. The BMQ-AET Specific Scale fitted the original 10 item model. Internal consistency of the BMQ-AET was much improved compared to the original BMQ and convergent validity showed predicted direction of correlation, although correlation with BMQ-AET concerns scale was low. Acceptability was good. The evaluation of the BMQ-AET is encouraging, and could facilitate future research around adherence to AET.

Hot Flushes or Flashes are a serious problem. They impact significantly on daily life and sleep quality, affecting employment, relationships and quality of life. The only effective treatment for hot flushes is oestrogen which is contraindicated in 75% of breast cancer patients. An estimated 550,000 people now live in the UK with a diagnosis of breast cancer and up to 70% women experience disabling hot flushes which can continue for years after treatment. Studies have shown that up to 50% of patients stop taking their life-saving antioestrogen drugs before 5 years1 quite probably due to unacceptable side-effects On the initiative of the patient advocate members of the NCRI Breast Clinical Studies Group, a Working Party on Symptom Management has been established. Members of the group have a particular interest in hot flushes and include representatives from patients, oncology, psychology, gynaecology, acupuncture and the voluntary not-for-profit sector The Working Party audited current UK clinical practice for hot flushes in cancer with a short questionnaire circulated to the UK Breast Intergroup mailing list (about 800 breast cancer health professionals) and to the Breast Cancer Care Nursing Network (about 850 clinical nurse specialists/breast care nurses). The full results of the questionnaire will be presented Briefly, a small number of people were prescribed hormone replacement therapy or Progesterone (Megestrol acatate), more Clonidine and Gabapentin and many selective serotonin reuptake inhibitors (SSRIs). Although SSRIs have some effect in reducing the intensity of hot flushes, they have significant side effects including sexual dysfunction, in a group of women, many of whom are already suffering sexual problems due to anti-oestrogen drugs or premature menopause. In addition, available treatments (both pharmacological and non-pharmacological) varied across the UK. The majority (95%) of respondents to our questionnaire agreed or strongly agreed that treatment and management of hot flushes is an unmet need. The questionnaire also demonstrated inequality of access to treatment in the UK. An exploration of the US National Cancer Institute and UK clinical trials databases revealed very few studies working in this area. 21 studies in the UK, Europe and the USA since 2006. Most trials investigate non pharmacological approaches and combinations and new versions of existing approaches. There are no agreed guidelines for managing hot flushes after breast cancer, which may limit the access and availability of appropriate interventions. It is clear from our survey that clinicians are left making individual decisions based on personal experience and availability of local services, which has led to a patchy and inequitable position on the management of this troubling problem. There is a need for research to understand the physiology of flushing and to develop and test new interventions to address this intractable problem, which continues to be a cause of considerable distress to many women after breast cancer. 1. Makubate B et al Cohort study of adherence to adjuvant endocrine therapy, breast cancer recurrence and mortality.Br J Cancer. 2013;108:1515-24. This project was funded by the National Institute for Health Research Health Technology Assessment (NIHR HTA) Programme (project number 10/34/01). The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the HTA programme, NIHR, NHS or the Department of Health. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P3-08-09.

The Breast Cancer Campaign Tissue Bank (BCCTB) was initiated in 2010 after the charity Breast Cancer Campaign heard from breast cancer experts that insufficient high quality breast cancer tissue was preventing research which would impact people with breast cancer1. The charity decided to involve patient advocates in the development of the BCCTB from the beginning. Two advocates reviewed the initial applications to form the BCCTB. These included both single and multi-centre applications so they suggested that, rather than choosing one centre to form the Bank, the charity consider a collaboration of centres. Throughout the development of the BCCTB, the patient advocates asked the ‘elephant in the room’ questions and brought a different perspective. They also helped to design the Bank's processes, including the consent process and asking that all tissue applicants produce a lay summary of their research. There are now two advocates on the Board which provides strategic direction to the BCCTB. The advocates have equal status to other Board members. There are also three advocates on the Tissue Access Committee which controls the use of tissue in the Bank. Lay summaries of projects have to be approved by all advocates before an application can proceed. This means that no precious tissue is released without the approval of a lay person, who can ensure maximum patient benefit will be achieved from any research. The Bank's data return policy was also driven by the patient advocates who were keen that the tissues donated were used to their maximum benefit. This has resulted in the first publication from BCCTB2 Patient advocates have been involved in promoting the use of tissue from the bank presenting at conferences and at BCCTB road shows. Patient advocates have also been involved in asking potential donors to consent to donate to the tissue bank. The involvement of patient advocates in the development and oversight of the BCCTB has shown researchers that patient and public involvement works. The advocates can also help promote the Bank and the benefits of tissue donation to both professionals and lay groups. The patient advocates involved in the Breast Cancer Campaign Tissue Bank are members of the charity Independent Cancer Patients’ Voice 1. Thompson P, Brennan K, Cox A, Gee J, Harcourt D, Harris A, Harvie M, Holen I, Howell A, Nicholson R, Steel M, Streuli C. Evaluation of the current knowledge limitations in breast cancer research: a gap analysis. Breast Cancer Res 2008: 10(2); R26. 2. Speirs V, Morgan A. Investment biobanking – increased returns on tissue samples. Nat Rev Clin Onc 2013; 10:128-129. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P1-10-01.

Adherence to adjuvant endocrine therapy (AET) following breast cancer is known to be suboptimal despite its known efficacy in reducing recurrence and mortality. This study aims to investigate factors associated with non-adherence and inform the development of interventions to support women and promote adherence. A questionnaire survey to measure level of adherence, side effects experienced, beliefs about medicine, support received and socio-demographic details was sent to 292 women 2–4 years post breast cancer diagnosis. Differences between non-adherers and adherers to AET were explored, and factors associated with intentional and unintentional non-adherence are reported. Approximately one quarter of respondents, 46 (22%), were non-adherers, comprising 29 (14%) intentional non-adherers and 17 (8%) unintentional non-adherers. Factors significantly associated with intentional non-adherence were the presence of side effects (p < .03), greater concerns about AET (p < .001) and a lower perceived necessity to take AET (p < .001). Half of the sample (105/211) reported that side effects had a moderate or high impact on their quality of life. Factors associated with unintentional non-adherence were younger age (

Follow-up after treatment for cancer currently varies widely depending on the hospital, surgeon, oncologist, cancer diagnosis and sometimes the wishes of the patient. There seems to be no gold standard. Some are followed up frequently with scans, blood tests and physical examinations for anything up to and beyond 10 years. Others are offered ‘open access’ or ‘patient-led’ follow-up and some are referred back to their general practitioner with a guarantee of rapid access back to hospital appointments in the event of signs of recurrence. This editorial addresses follow-up and related survivorship issues from the patient’s view point.

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...

Women who have been treated for breast cancer identify vasomotor symptoms, such as hot flushes and night sweats, as a serious problem. These symptoms can be unpleasant, with a significant impact on daily life and sleep quality: It’s as though somebody has built a furnace inside of you and it’s your whole body. It starts almost at your feet and works up and you just feel as though you are literally on fire inside and it’s trying to escape and you just want to escape but you can’t escape, there’s nowhere to go and nothing to do [1]. The social consequences of this embarrassing experience can affect employment, personal relationships and quality of life: Umm, when they were at their worst I would be yeah pretty much dripping in, in err, various places umm err from really from the nose downwards; the lips; the neck; umm chest and back; crooks of my arms. And I could, you know, often if I was sitting down I would get up and my trousers would be really wet and it would go right down to my toes [1]. Oestrogen replacement remains the most effective treatment for hot flushes. However, this is contraindicated in the majority of women with oestrogen-dependent breast cancer. An estimated 550 000 people live in the UK today with a diagnosis of breast cancer and up to 70% experience hot flushes [2e5], which are exacerbated by a lack of safe and effective management strategies [4]. Although hot flushes may occur for a number of reasons, including natural or chemotherapy-induced menopause, they may also be side-effects of adjuvant hormonal therapies, such as tamoxifen and the aromatase inhibitors. Two recent clinical trials (aTTom [6] and ATLAS [7]) showed that 10 years of tamoxifen significantly reduces the risk of recurrence and breast cancer mortality. However, an increasing number of studies report that over 50% of women do not adhere to 5 years of endocrine treatment with an associated increase in mortality [8]. The lack of effective management of vasomotor symptoms may be an important contributory factor to this lack of adherence [9]. The pathophysiology of hot flushes is poorly understood. Proposed mechanisms include altered peripheral vascular reactivity and a narrowed thermoneutral zone [10], although how this relates to oestrogen deprivation is not understood. Without a fuller understanding of the physiology, mechanisms and triggers it will be difficult to develop new targeted therapies. Adrienne Morgan says ‘I was diagnosed with breast cancer eight years ago and continue to take anti-oestrogen drugs because my cancer has returned. I have had a hot flush every 45 minutes for the last eight years. It is difficult to convey to anyone who has never had a hot flush how awful they are; exhausting, embarrassing, agitating.. I am fatigued, unable to work, sleep is only possible with medication and every morning my bed is soaked. I have tried everything. Only the SSRIs have some effect by reducing the severity of the hot flushes (venlafaxine made me feel horrible so I take Citalopram)but they make me anorgasmic. It surprises me that there is not more basic research being done into the causes of hot flushes. After all, most women will have them at some stage in their lives - not just breast cancer patients - and now men with prostate cancer are getting them too’.

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.

Researchers now expect that samples obtained from biobanks are accompanied with well-annotated clinical data. Opened in 2010, the Breast Cancer Campaign Tissue Bank takes this criterion a step further: researchers obtaining tissues are required to return the data they generate from every sample back to the Tissue Bank.

TPS656 Background: Chemotherapy may have little effect on some subtypes of early breast cancer, identified as being hormonally responsive tumours without HER2 gene amplification and with a low or intermediate grade. Multi-parameter genomic tests such as Oncotype DX are increasingly used to identify patients for whom the addition of chemotherapy may confer little additional benefit. OPTIMA has an adaptive design seeking to advance development of personalised medicine in breast cancer by assessing the value of multi-parameter tests in a UK population of intermediate risk. Methods: OPTIMA prelim, the feasibility phase, has 3 objectives: (1) To evaluate performance and health-economics of multi-parameter tests to determine which test(s) will be used in the main trial; (2) To establish efficient and timely sample collection and analysis essential to deliver multi-parameter test driven treatment; (3) To establish the acceptability to patients and clinicians of randomisation to test-directed treatment assignment. OPTIMA prelim aims to recruit 300 patients with ER+ve HER2-ve tumours with involved nodes (pN1-2). Patients are randomized to the standard arm of chemotherapy with endocrine therapy, or to the “test-directed treatment” arm assigned to either the same chemotherapy with endocrine therapy or endocrine therapy only according to the result of an Oncotype DX test. The decision to continue to a main trial will be determined by concordance, cost and willingness of patients to be randomized to test guided treatment. Cost-effectiveness models will be based on the model developed in preparation for the OPTIMA trial, updated with contemporary evidence from the feasibility study and appropriate external data, e.g. the Ontario prospective cohort study. Results: Optima opened in Sept 2012 with 25 centres involved. To date 22 patients are registered, of which 17 have been randomised. Patient focus groups show the trial design is acceptable and has potential to reduce need for chemotherapy. TSC and DMEC agree that this is an important trial testing the feasibility within this patient population. Decision rules are challenging for this study but employment of adaptive designs gives the flexibility needed for the main trial. Clinical trial information: ISRCTN42400492.

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.