500 Background: Tumor gene expression tests are widely used to assist adjuvant chemotherapy decisions for women with early breast cancer (EBC). OPTIMA (Optimal Personalised Treatment of early breast cancer using Multi-parameter Analysis) is an international RCT comparing chemotherapy decisions made with the Prosigna (PAM50) gene expression test with standard treatment in mostly node-positive patients. Methods: Women and men aged >40 recommended to receive chemotherapy for ER+ HER2- EBC with 0-9 involved axillary nodes and T size >30mm if node negative were eligible. Randomization was between standard chemotherapy followed by endocrine therapy (CET) or to a Prosigna test directed chemotherapy decision. Patients with Prosigna ROR score > 60 tumors were assigned CET whilst those with low ROR score (≤60) tumors received endocrine therapy (ET) alone. ET for premenopausal women included ovarian function suppression (OFS) in the absence of chemotherapy-induced ovarian insufficiency. ROR scores were not disclosed, and patients receiving CET were blinded to their randomization. OPTIMA was designed to demonstrate non-inferiority (NI) of 5-year invasive breast cancer free survival (IBCFS) in the test-directed arm with a 3% margin in the per protocol (PP) population using a 5% 1-sided alpha. Control arm testing allowed treatment comparison within the low ROR score population at a 3.5% NI margin. Results: From 16 th Jan 2017 to 12 th Dec 2025 4429 patients were randomized, 2215 to the control arm and 2214 to the test-directed arm of whom 2061 (93%) and 2097 (95%) were included in the respective PP group. Patient characteristics in the PP population were well-balanced; 62% were postmenopausal, 37% premenopausal and 0.8% male. 73% had pN1/pN1sn, 8% had pN0/pN1mi and 19% had pN2 tumors. 68% had low ROR score tumors. With a median follow-up of 3.9 years (interquartile range 2.0-5.9), 280 IBCFS events occurred (141 on control arm; 139 on test directed arm) of which 66% were distant recurrences. The 5-year IBCFS rate in the control arm was 91.5% [95% CI 89.7- 92.9%] and 90.4% [95% CI 88.6- 92.0%] in the test-directed arm, Hazard Ratio (HR) 0.99 [90% CI 0.81- 1.20], NI p = 0.013, thereby meeting the pre-defined NI margin. The corresponding 5-year IBCFS rates for the low ROR score population were 94.9% [95% CI 92.9- 96.4%] and 93.7% [95% CI 91.8- 95.2%] for the two arms respectively, HR 1.06 [90% CI 0.78- 1.46] NI p = 0.0051 again demonstrating non-inferiority. There was no significant outcome heterogeneity between subgroups including for menopausal and nodal status. Conclusions: The OPTIMA trial demonstrates that women and men with ER+ HER2- EBC and ROR score ≤60 tumors can safely avoid chemotherapy. It provides evidence for the utility of test-directed chemotherapy in premenopausal women treated with OFS and patients with high levels of nodal involvement. Clinical trial information: ISRCTN42400492.

Abstract Background Strong PgR expression predicts favorable outcomes for ER+ve HER2-ve breast cancer and has been proposed as a surrogate marker to distinguish between IHC-defined luminal A and luminal B subtypes. It is therefore possible that strong PgR expression may be able to predict tumor gene expression test results and independently identify tumors that are unlikely to be chemotherapy sensitive. PgR expression is traditionally determined by immunohistochemistry (IHC). Several validated RNA-based PGR expression tests have been developed that may outperform IHC. Methods We compared Oncotype DX RS with Oncotype DX reported PGR in 4 independent datasets which included 407 cases from the OPTIMA prelim trial. We further analyzed 251 OPTIMA prelim cases which had additional tumor gene expression data. All gene expression assays were performed by the test vendor, including PGR gene expression determined using the Mammatyper assay. PgR IHC was determined in a single laboratory on triplicate tissue micro-arrays using quantitative image analysis including a 10% manual quality control check. We analyzed PGR expression using cutoffs that correspond to approximately 20% staining; the standard Oncotype DX PGR assay is reported as positive if the score is >5.4, corresponding to approximately 1% staining by IHC. We used Spearman’s rank correlation coefficient to compare PGR data. Results The four Oncotype DX datasets consistently demonstrated that high Oncotype PGR expression was associated with a low RS (table). Combining the 3 validation data sets consisting of 633 cases, 70.9% had high PGR expression of which 92.7% had a an Oncotype RS ≤25. Approximately 50% of cases with low Oncotype PGR expression had an Oncotype RS >25. Mammatyper and Oncotype PGR were highly correlated (Rs = 0.9258, P< 0.001) in the OPTIMA prelim dataset (n=251), with only 8.4% of tumors having discordant high/low Mammatyper and Oncotype PGR scores. 93.2% of 176 Mammatyper high PGR expression cases had an RS ≤25. The Mammatyper PGR and PgR IHC correlation was weaker (Rs=0.763, P< 0.001); 87.2% of 211 cases with >20% staining had RS ≤25. PgR IHC staining had a bimodal distribution and there was little effect on the prediction of low RS score up to a 67% cut-off. Mammatyper and Oncotype PGR scores both appear to have a normal distribution. We took advantage of this to perform an exploratory analysis using a higher Mammatyper PGR cutoff. We were able to show superior prediction of a low RS (96.8%) but with a reduced proportion (50.2%) of high PGR score tumors. High PGR gene expression was weakly associated with low (≤60) Prosigna ROR_PT score and MammaPrint low risk (72.2% and 65.9% respectively) and with Prosigna and MammaPrint luminal A subtype (both 64.8%). Conclusion High progesterone receptor gene expression measured using locally performed RNA-based assays may allow the reliable prediction of Oncotype DX low-risk tumours. This analysis provides additional information for the clinical utility of PGR measurement. Additional data will be presented on the optimal PGR cutoff. OPTIMA prelim is registered as ISRCTN42400492 and funded by the UK NIHR Health Technology Assessment Programme, award number 10/34/01. Views expressed are those of the authors and not those of the HTA Programme, NIHR, NHS or the Department of Health. Table. Oncotype DX RS and PGR in 4 datasets Distribution of RS according to %cases with high or low PGR Citation Format: Robert Stein, Ralph Wirtz, Andrea Marshall, Jane Bayani, Sebastian Eidt, Claudia Schumacher, Hans-Peter Sinn, Andreas Schneeweiss, Andreas Makris, Iain Macpherson, Luke Hughes-Davies, Tammy Piper, Monika Sobol, Georgina Dotchin, Helen Higgins, Sarah Pinder, Abeer Shaaban, Janet Dunn, John MS Bartlett. Can high progesterone receptor (PgR) expression identify tumours with low-risk tumour gene expression scores? [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-16-02.

Background: Multi-parameter tumor gene expression assays (MPAs) are used to estimate individual patient risk and 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 postmenopausal node-positive breast cancer has been provided by the RxPONDER trial interim analysis but this relies on the absence of superiority in an analysis where >50% of events were unrelated to breast cancer. There is much uncertainty about MPA use for premenopausal patients. OPTIMA (Optimal Personalised Treatment of early breast cancer usIng Multi-parameter Analysis) (ISRCTN42400492) is a prospective international randomized controlled trial designed to validate MPAs 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 trial recruits women and men age 40 or older with resected ER-positive, HER2-negative invasive breast cancer and up to 9 involved axillary lymph nodes. Randomization is to standard management (chemotherapy and endocrine therapy) or to MPA-directed treatment using the Prosigna (PAM50) test. Those with a Prosigna tumor Score (ROR_PT) >60 receive standard management whilst those with a low score (≤60) tumor are treated with endocrine therapy alone. Endocrine therapy for pre-menopausal women includes ovarian suppression for all participants unless they experience a chemotherapy-induced menopause. Adjuvant abemaciclib is permitted. The trial will be analyzed for (1) non-inferiority of recurrence according to randomization and (2) cost-effectiveness. The key secondary outcome is non-inferiority of recurrence for patients with low ROR_PT score tumors. The efficacy analyses will be performed Per Protocol using Invasive Breast Cancer Free Survival (IBCFS) as the primary outcome measure to limit the risk of a false non-inferiority conclusion. Recruitment of 4500 patients over 8 years will permit demonstration of up to 3% non-inferiority of test-directed treatment with at least 83% power, assuming 5-year IBCFS is 87% 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. OPTIMA is strongly supported by a patient group which has helped design all patient documents and which is represented on the TMG. Results: The OPTIMA main trial opened in January 2017 and has continued to recruit throughout the COVID-19 pandemic. Overall recruitment as of 1 July 2022 was 2814 (2593 from UK, 221 from Norway). Patient characteristics are well balanced between the trial arms. Currently 95% of randomized participants are eligible for inclusion in the PP analysis. 66% of the MPA-directed arm participants have been allocated to endocrine therapy only. The test failure rate is < 1%. Conclusion: OPTIMA will provide robust unbiased evidence on test-directed chemotherapy safety for both postmenopausal and premenopausal women with 1-3 involved nodes as well as for patients with 4-9 involved nodes and for patients treated with abemaciclib. Funding: OPTIMA is funded by the UK NIHR HTA Programme (10/34/501) and in Norway by KLINBEFORSK and the Norwegian Cancer Society. 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 Patient characteristics Citation Format: Robert Stein, Andreas Makris, Iain Macpherson, Luke Hughes-Davies, Andrea Marshall, Georgina Dotchin, David A. Cameron, Belinda E. Kiely, Caroline Wilson, Anne Armstrong, Helena M. Earl, Christopher J. Poole, Janice Tsang, Bjørn Naume, Daniel Rea, Hege Ohnstad, Peter S. Hall, Stuart A. McIntosh, Bethany Shinkins, Christopher McCabe, Adrienne Morgan, 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 high clinical risk early breast cancer. [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT3-32-01.

567 Background: Tumor gene expression tests are increasingly used in breast cancer management. The Ki67 biomarker has been proposed as an inexpensive alternative for making chemotherapy decisions, has demonstrated utility for determination of endocrine therapy responsiveness and is included in the FDA license for adjuvant abemaciclib. We have compared Ki67 measurements with tumor gene expression test results for patients included in the OPTIMA prelim trial. Methods: We compared Ki67 %staining with the results of Oncotype DX, Prosigna and MammaPrint performed by the test vendor. Ki67 was determined in a single laboratory on triplicate tissue micro-arrays using quantitative image analysis including a 10% manual quality control check. We used kappa statistics to measure agreement between tests, divided into groups using the pre-defined test score boundaries for high vs. not high risk. Results: Data were available for 259 patients. Using ≥20% staining to define a high Ki67 score, kappa values (95% CI) for agreement with Prosigna were: 0.39 (0.28-0.49); Oncotype DX: 0.27 (0.18-0.36); and MammaPrint: 0.38 (0.27-0.49). Kappa values <0.2 are conventionally interpreted as showing slight agreement and 0.21-0.4 as fair agreement. A detailed breakdown of the comparisons of Ki67 with Prosigna and Oncotype DX is tabulated. Conclusions: Agreement between Ki67 and tumor gene expression tests is limited. Therefore, Ki67 values cannot accurately be used to reflect any of the molecular scores assessed here, all of which are well validated prognostic biomarkers. The use of Ki67 to determine suitability for adjuvant chemotherapy requires validation before it can replace the existing tests. Tumor gene expression tests may prove superior to Ki67 for the identification of patients likely to benefit from adjuvant abemaciclib. OPTIMA prelim is registered as ISRCTN42400492 and funded by the UK NIHR Health Technology Assessment Programme, award number 10/34/01. Clinical trial information: ISRCTN42400492. [Table: see text]

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.

BackgroundThe addition of adjuvant trastuzumab to chemotherapy has significantly improved outcomes for people with human epidermal growth factor receptor 2 (HER2)-positive, early, potentially curable breast cancer. Twelve months’ trastuzumab, tested in registration trials, was adopted as standard adjuvant treatment in 2006. Subsequently, similar outcomes were demonstrated using 9 weeks of trastuzumab. Shorter durations were therefore tested for non-inferiority.ObjectivesTo establish whether or not 6 months’ adjuvant trastuzumab is non-inferior to 12 months’ in the treatment of HER2-positive early breast cancer using a primary end point of 4-year disease-free survival.DesignThis was a Phase III randomised controlled non-inferiority trial.SettingThe setting was 152 NHS hospitals.ParticipantsA total of 4088 patients with HER2-positive early breast cancer who it was planned would receive both chemotherapy and trastuzumab took part.InterventionRandomisation (1 : 1) to 6 months’ or 12 months’ trastuzumab treatment.Main outcomesThe primary end point was disease-free survival. The secondary end points were overall survival, cost-effectiveness and cardiac function during treatment with trastuzumab. Assuming a 4-year disease-free survival rate of 80% with 12 months’ trastuzumab, 4000 patients were required to demonstrate non-inferiority of 6 months’ trastuzumab (5% one-sided significance, 85% power), defining the non-inferiority limit as no worse than 3% below the standard arm. Costs and quality-adjusted life-years were estimated using a within-trial analysis and a lifetime decision-analytic model.ResultsBetween 4 October 2007 and 31 July 2015, 2045 patients were randomised to 12 months’ trastuzumab and 2043 were randomised to 6 months’ trastuzumab. Sixty-nine per cent of patients had ER-positive disease; 90% received anthracyclines (49% with taxanes; 41% without taxanes); 10% received taxanes without anthracyclines; 54% received trastuzumab sequentially after chemotherapy; and 85% received adjuvant chemotherapy (58% were node negative). At 6.1 years’ median follow-up, with 389 (10%) deaths and 566 (14%) disease-free survival events, the 4-year disease-free survival rates for the 4088 patients were 89.5% (95% confidence interval 88.1% to 90.8%) in the 6-month group and 90.3% (95% confidence interval 88.9% to 91.5%) in the 12-month group (hazard ratio 1.10, 90% confidence interval 0.96 to 1.26; non-inferiorityp = 0.01), demonstrating non-inferiority of 6 months’ trastuzumab. Congruent results were found for overall survival (non-inferiorityp = 0.0003) and landmark analyses 6 months from starting trastuzumab [non-inferiorityp = 0.03 (disease-free-survival) andp = 0.006 (overall survival)]. Six months’ trastuzumab resulted in fewer patients reporting adverse events of severe grade [365/1929 (19%) vs. 460/1935 (24%) for 12-month patients;p = 0.0003] or stopping early because of cardiotoxicity [61/1977 (3%) vs. 146/1941 (8%) for 12-month patients;p < 0.0001]. Health economic analysis showed that 6 months’ trastuzumab resulted in significantly lower lifetime costs than and similar lifetime quality-adjusted life-years to 12 months’ trastuzumab, and thus there is a high probability that 6 months’ trastuzumab is cost-effective compared with 12 months’ trastuzumab. Patient-reported experiences in the trial highlighted fatigue and aches and pains most frequently.LimitationsThe type of chemotherapy and timing of trastuzumab changed during the recruitment phase of the study as standard practice altered.ConclusionsPERSEPHONE demonstrated that, in the treatment of HER2-positive early breast cancer, 6 months’ adjuvant trastuzumab is non-inferior to 12 months’. Six months’ treatment resulted in significantly less cardiac toxicity and fewer severe adverse events.Future workOngoing translational work investigates patient and tumour genetic determinants of toxicity, and trastuzumab efficacy. An individual patient data meta-analysis with PHARE and other trastuzumab duration trials is planned.Trial registrationCurrent Controlled Trials ISRCTN52968807, EudraCT 2006-007018-39 and ClinicalTrials.gov NCT00712140.FundingThis project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full inHealth Technology Assessment; Vol. 24, No. 40. See the NIHR Journals Library website for further project information.

Abstract 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 <1%. 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.

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: 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 clinicians9 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.

Helena M Earl, Louise Hiller, Anne-Laure Vallier, Shrushma Loi, Karen McAdam, Luke Hughes-Davies, Adrian N Harnett, Mei-Lin Ah-See, Richard Simcock, Daniel Rea, Sanjay Raj, Pamela Woodings, Mark Harries, Donna Howe, Kerry Raynes, Helen B Higgins, Maggie Wilcox, Chris Plummer, Janine Mansi, Ioannis Gounaris, Betania Mahler–Araujo, Elena Provenzano, Anita Chhabra, Jean E Abraham, Carlos Caldas, Peter S Hall, Christopher McCabe, Claire Hulme, David Miles, Andrew M Wardley, David A Cameron, Janet A Dunn on behalf of PERSEPHONE Steering Committee and Trial Investigators*

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, p< 0.0001). Interpretation 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. Copyright (C) 2019 The Author(s). Published by Elsevier Ltd.