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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.

Introduction Breast cancer is uncommon in men. Almost all male breast cancers are hormone receptor-positive, HER2-negative, although the pathogenesis is not always attributable to an endocrine condition. A few studies have compared biological characteristics or molecular signatures with breast cancers in women. We sought to evaluate whether hormone receptor-related gene expression is different in cancers from men compared to equivalent cancers from women. SET2,3 index measures non-proliferative hormone receptor-related transcriptional activity in the cancer (SET-ER/PR index) and adjusts this for a Baseline Prognosis Index (BPI) that combines the measurements of tumor and nodal stage with a 4-gene molecular subtype (ESR1, PGR, ERBB2, and AURKA). Methods We received aliquots of total RNA from male patients with breast cancer included in the retrospective cohort study of the EORTC 10085/BCG/TBCRC/BIG/NCTN International Male Breast Cancer Program (NCT01101425). SET2,3 assay was performed using the QuantiGene assay (Thermo Fisher) using bead-based hybridization and laser spectroscopy (Luminex). The statistical analyses were performed by the EORTC statistician. The primary objective of the study was the assessment of the prognostic value of the SET2,3 index score in patients with early-stage hormone receptor-positive, HER2-negative male breast cancer, treated with endocrine therapy. Clinical outcomes (recurrence-free survival – RFS; overall survival – OS) were estimated by Kaplan-Meier curves and secondarily compared using multivariable Cox models adjusted for continuous SET2,3 index, tumor size, nodal status, age, and chemotherapy and radiotherapy use. An exploratory analysis to compare the SET2,3 index scores distribution in female and male breast cancer patients was also performed using results from the same assay performed on cancers from women selected on the same inclusion criteria. Due to the low numbers of male patients treated with neoadjuvant treatment (N=6), this analysis was restricted to patients treated with adjuvant treatment (n=315 male and 660 female). Results Of the 321 male patients with breast cancer analyzed, treated between 1990 and 2010, 211 (65.7%) were categorized as high SET2,3 index score, reflecting a high endocrine activity in the cancer and low risk of recurrence, and 110 patients (34.3%) categorized as being low score, reflecting low endocrine activity and high risk of recurrence. At 5 years, the RFS was 75.0% (95% CI, 67.4-81.1) in the high SET2,3 group versus 60.7% (95% CI, 49.1-70.5) in the low SET2,3 group (HR univariate, 0.49; 95% CI, 0.34-0.70; P< 0.0001). The 5-year OS rate among patients with a high SET2,3 index was 84.3% (95% CI, 45.5-73.8), in contrast of 67.8% (95% CI, 56.6-76.7) in the low SET2,3 group (HR univariate, 0.44; 95% CI, 0.30-0.65; P< 0.0001). SET2,3 was independently prognostic for OS, but not RFS in multivariable Cox models. In patients classified as low SET2,3, the addition of neo/adjuvant chemotherapy to adjuvant endocrine therapy was associated with 5-year OS of 76.0% (95% CI, 59.5-86.4) and in patients who received endocrine therapy alone the 5-year OS was 61.3% (95% CI, 45.5-73.8), an absolute difference of 14.7 percentage points. Overall, we did not observe a difference in the distributions (median, interquartile range) of SET2,3 index between men (2.4, 1.9–2.6) and women (2.3, 2.0–2.7). Conclusion SET2,3 index measurements of endocrine-related transcriptional activity in male patients with breast cancer were not different from measurements in female patients with breast cancer. SET2,3 was prognostic in male breast cancer and our exploratory analysis suggests that chemotherapy might improve the poor prognosis for men with breast cancer that has low SET2,3 index. This study was funded by the Breast Cancer Research Foundation (BCRF). Citation Format: Danielle B. Zakon, Coralie Poncet, Fatima Cardoso, Neven Anouk, Vicente Valero, Stefan Aebi, Kim Benstead, Oliver Bogler, Lissandra Dal Lago, Judith Fraser, Carmela Caballero, Ingrid A. Hedenfalk, Larissa A. Korde, Barbro Linderholm, John WM Martens, Lavinia P. Middleton, Melissa Murray, Catherine M. Kelly, Cecilia Nilsson, Monika Nowaczyk, Stephanie Peeters, Melanie Beauvois, Peggy Porter, Carolien P. Schroder, Isabel T. Rubio, Kathryn Ruddy, Christi van Asperen, Danielle Van Den Weyngaert, Carolien HM van Deurzen, Elise van Leeuwen-Stok, Joanna M. Vermeij, John MS Bartlett, Antonio C. Wolff, Sharon H. Giordano, W. Fraser Symmans. PD6-11 Evaluation of the Sensitivity to Endocrine Therapy Index (SET2,3) in Early Male Breast Cancer: Results from an analysis in the EORTC 10085/TBCRC/BIG/NCTN International Male Breast Cancer Program [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 PD6-11.

Background: Women with HR+ breast cancer experience a persistent risk of distant recurrence (DR) even after completion of 5 years of adjuvant endocrine therapy, with more than 50% of DR occurring after 5 years (late DR). The prognostic genomic signatures currently being used in the clinic were not developed or optimized specifically for late DR. We have previously shown that the Breast Cancer Index (BCI) and BCIN+ prognostic models were significantly prognostic for risk of overall (0-10y) and late (5-10y) distant recurrence (DR) in N0 and N1 HR+ patients in the Tamoxifen and Exemestane Adjuvant Multinational (TEAM) trial. Here, the prognostic performance of the BCI and BCIN+ models with alternative cut-points optimized for late DR were evaluated in patients from the TEAM trial, who were free from DR for at least 5 years. Methods: BCI testing was performed blinded to clinical outcome. The pre-specified alternative cut-points 4.4 and 1.8 for BCI and BCIN+ models were determined previously from Trans-aTTom and IDEAL studies, respectively (ESMO 2021). Kaplan-Meier analysis and log-rank test were used to evaluate the prognostic significance of BCI/BCIN+ risk groups based on DR. Univariate and multivariate Cox models were used to estimate hazard ratios (HRs) and the associated 95% confidence intervals (CIs). Results: 1285 HR+ N0 (median age 69.2, 54.2% T1, 92.5% G2-3, 21.3% chemotherapy) and 1762 N1 (median age 68.5, 49.7% T1, 80.8% G2-3, 42.6% chemotherapy) patients who remained free from DR at 5 years post randomization were included in the current analysis. For N0 patients, BCI identified 439 (34%) and 846 (66%) patients as low and high-risk with late 10-year DR rates of 3.8% (95% CI: 1.5-6.0%) and 9.1% (95% CI: 6.8-11.4%), respectively (HR: 2.6, 95% CI: 1.4-5.0; p=0.0025). For N1 patients, BCIN+ identified 287 (16%) and 1475 (84%) patients as low and high-risk with late 10-year DR rates of 3.4% (95% CI: 1.2-5.5%) and 12.3% (95% CI: 10.4-14.2%), respectively (HR: 3.5, 95% CI: 1.8-6.9; p< 0.0001). Similar results were observed in the HER2- patients. Notably, BCI/BCIN+ remained a statistically significant prognostic factor in the multivariate analysis after controlling for age, tumor size, grade, treatment. (Table). Conclusions: Compared to the original BCI/BCIN+ models, the optimized BCI and BCIN+ models showed improved prognostic performance for identifying low-risk patients with a very low risk of late DR (< 4%), for both N0 and N1 patients. These results provide further validation of BCI clinical utility as an aid in the decision-making for extended endocrine therapies for HR+ breast cancer, particularly in patients with N1 disease that may be spared extended endocrine treatment. Table Citation Format: John MS Bartlett, Keying Xu, Jenna Wong, Gregory R. Pond, Yi Zhang, Melanie Spears, Ranelle Salunga, Elizabeth Mallon, Karen J. Taylor, Annette Hasenburg, Christos Markopoulos, Luc Dirix, Caroline Seynaeve, Cornelis J.H. van de Velde, Daniel Rea, Catherine A. Schnabel, Kai Treuner, Jane Bayani. Validation of the Breast Cancer Index (BCI) prognostic models optimized for late distant recurrence in postmenopausal women with early-stage HR+ breast cancer in the TEAM trial [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 P2-11-10.

Background: Adjuvant whole breast radiotherapy (RT) is provided to almost all women with early-stage invasive breast cancer after breast conserving surgery and appropriate systemic therapy. While there is increasing interest to personalize the use of RT based on molecular profiling, to date, there is no molecular signature available to reliably assess the benefit of radiotherapy after surgical resection. Here we assess the ability of a 16-gene signature named Profile for the Omission of Local Adjuvant Radiotherapy (POLAR) to identify who may be suitable candidates for radiotherapy omission in patients of the Scottish Conservation Trial. Methods: The POLAR signature was applied to archival tissue from the Scottish Conservation Trial, which randomized 585 patients with stage I-II breast cancer, tumor size < 4 cm, and age ≤70 years old to receive RT or not. The archival tissue was measured for ER (ER+ >10%), PgR (PgR+ ≥20%), Ki67 (Ki67 high ≥14%), and HER2 (HER2+ defined as HER2 over-expressed or amplified). 26% received adjuvant chemotherapy, the remainder received tamoxifen 20 mg/daily for 5 years. Cox models for the locoregional recurrence (LRR) endpoint tested the association between treatment arms separately for patients with a low and high POLAR score using a pre-specified cut point. Cumulative incidences were computed, with distant metastasis and death without recurrence considered competing events. Results: 224 patients had tissue available and complete clinical data for analysis, 40 (18%) were node-positive. The distribution of clinicopathologic variables between the RT and no RT arms remained balanced. 43% were ER+/PgR+/Ki67 low/HER2-, 31% were ER+/HER2-/Ki67 high or PgR-, 5% were HER2+, and 13% were triple negative. The continuous standardized POLAR score was prognostic for LRR in the no RT arm after adjusting for relevant covariates (HR=1.78 [1.20-2.64], p=0.003). For patients with a POLAR-high score, the 10-year LRR rate was 31% [21%-42%] for patients not receiving RT and 8% [3%-15%] for patients receiving RT (HR 0.36 [0.19-0.69], p=0.0022). For patients with a POLAR low score, the 10-year LRR rates were 20% [10%-33%] for patients not receiving RT and 6% [1%-18%] for patients receiving RT; HR=0.28 [0.08-0.98], p=0.046). In the subgroup of node-negative patients with ER+/HER2-negative tumors (N=137), there was a statistically significant RT benefit for patients with a POLAR high score (HR=0.31 [0.11-0.88], p=0.028) but not for patients with a POLAR low score (HR=0.5 [0.1-2.4], p=0.39). Conclusions: For patients with early-stage invasive breast cancer treated with breast-conserving surgery without RT, POLAR is prognostic for LRR and may refine the selection of “low risk” for omission of RT. Citation Format: Karen J. Taylor, John MS Bartlett, John Bennett, S. Laura Chang, Bradley Arrick, Frederick Baehner, Joseph F. Loane, Tammy Piper, Elizabeth Mallon, Joanna Dunlop, Wilma J. Jack, Jacqueline Caldwell, Ian Kunkler, Linda J. Williams, Corey W. Speers, Felix Y. Feng, Lori Pierce, David A. Cameron. Validation of Profile for the Omission of Local Adjuvant Radiotherapy (POLAR) in early-stage invasive breast cancer patients of the Scottish Conservation Trial [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 P4-02-12.

Background: There are currently no commercially available tests to identify early stage breast cancer patients treated with breast conserving surgery (BCS) and systemic therapy at low risk of locoregional recurrence (LRR) for whom postoperative radiotherapy (RT) may be safely omitted. Profile for the Omission of Local Adjuvant Radiotherapy (POLAR) is a 16-gene molecular signature developed to identify invasive breast cancer patients who may be candidates for RT omission after BCS. In this work, we seek to validate POLAR in a meta-analysis of three RCTs of BCS +/- RT: SweBCG91RT, Scottish Conservation Trial (SCT) and Princess Margaret Hospital (PMH). Methods: A patient-level meta-analysis was performed in 623 node-negative breast cancer patients with ER+/HER2-negative tumors who were enrolled in the three RCTs and for whom primary tumor material was available for analysis. Contributions from each cohort were as follows: SweBCG91RT N=354 (57%), SCT N=137 (22%), and PMH N=132 (21%). Numbers of LRR events in each cohort were as follows: SweBCG91RT N=72 (20%), SCT N=28 (20%), and PMH N=16 (12%). There was a mix of systemic therapy used (no systemic therapy for SweBCG91RT, chemotherapy or adjuvant endocrine therapy, but not both, in SCT, and tamoxifen but no chemotherapy for PMH). Median follow-up time for the patients who did not have LRR was 13.3 years for SweBCG91RT, 21.1 years for SCT, and 8.6 years for PMH. A multivariable Cox proportional hazards model on time to LRR, including the continuous standardized POLAR score, RT, and interaction, stratified by cohort, was used to test the interaction between the continuous POLAR score and RT. Additional Cox models tested the association between treatment arms separately for patients with a low and high POLAR score using a pre-specified cut point. Cumulative incidences were computed, with distant metastasis and death without recurrence considered as competing events. Results: The test for interaction between RT treatment and POLAR was statistically significant (p = 0.022). Patients with a high POLAR score (N=429 [69%]) had a large benefit from RT (10-year cumulative incidence of LRR: 20% [15%-26%] for those not treated with RT vs 7% [4%-11%] for those treated with RT; hazard ratio for RT vs no RT: 0.37 [0.23-0.60], p < 0.001), whereas there was no evidence of benefit from RT for patients with a low POLAR score (N=194 [31%], 10-year cumulative incidence of LRR: 5% [2%-11%] for those not treated with RT vs 7% [3%-14%] for those treated with RT; hazard ratio for RT vs no RT: 0.92 [0.42-2.02], p = 0.832). Conclusions: To our knowledge, POLAR is the first genomic classifier that is not only prognostic for LRR but also predictive, showing a significant interaction between RT and the classifier. Patients with a high POLAR score should be recommended radiotherapy while patients with a low score may be candidates for omission of radiotherapy after breast conserving surgery. Citation Format: Per Karlsson, Anthony Fyles, S. Laura Chang, Bradley Arrick, Frederick Baehner, Per Malmström, Mårten Fernö, Erik Holmberg, Martin Sjöström, Fei-Fei Liu, David A. Cameron, Linda J. Williams, John MS Bartlett, Joanna Dunlop, Jacqueline Caldwell, Joseph F. Loane, Elizabeth Mallon, Tammy Piper, Wilma J. Jack, Ian Kunkler, Felix Y. Feng, Corey W. Speers, Lori Pierce, John Bennett, Karen J. Taylor. Validation of Profile for the Omission of Local Adjuvant Radiotherapy (POLAR) in a meta-analysis of three randomized controlled trials of breast conserving surgery +/- radiotherapy [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 GS4-03.

Background: Window of opportunity (WOO) clinical trials take advantage of the waiting period between a patient’s cancer diagnosis and standard treatment (usually surgery) to evaluate novel cancer therapies and their biologic effects in vivo. These types of trials are being increasingly harnessed in the clinical setting for the safe and rapid evaluation of novel therapeutic strategies in treatment naive patients, thereby expediting drug development. Distinct from neoadjuvant trials, no therapeutic benefit is envisaged and the patient’s standard treatments are not intentionally delayed. The purpose of this study was to understand the patient motivations and perspectives for participating in WOO trials. Methods: This study was conducted at an academic cancer center where two breast cancer WOO trials were ongoing (NCT04781725 and NCT04676516). Eligible patients with newly diagnosed operable invasive breast cancers participating in either of these WOO trials were recruited to this separate study. Patients were provided with a questionnaire that surveyed their motivation and perspectives for participation or lack of participation in the WOO trial Results: From April 2021- May 2022, the study recruited 89 patients with age ranging from of 40-78 yrs with tumors ranging from 1.5-4.3 cm. Surgical wait times ranged from 2-8 weeks. Of the 83 patients that participated in a WOO trial, the most common reasons for participation included (a) the potential to benefit other patients in the future (90%) (b) trust in their treating doctor (88%), (c) desire to contribute to scientific research (62%) and (d) a belief that they may benefit from the therapy (39%). For these patients, 49% reported that the possibility of a repeat biopsy would not deter them from trial participation; whereas 11% said that it definitely would. Of the 6 patients that chose not to participate in a WOO trial the most common reasons included (a) travel or transportation issues (50%) and (b) lack of belief of potential benefit to them (33%). For these patients, when asked whether the participation of a cancer patient in the design of the WOO trial would change their mind, all reported that it would not make a difference. Conclusion: WOO trials are becoming increasingly common in oncology research. Understanding patient perspectives for WOO trial participation is useful to inform trial design and communication approaches in future WOO trial efforts. Citation Format: Vanessa Lopez Ozuna, Gregory R. Pond, John MS Bartlett, Lazlo Radvanyi, Melanie Spears, Teresa Petrocelli, Carol Gordon, Rebecca J. Rose, Angel Arnaout. Understanding Patient Perspectives on Window of Opportunity Clinical Trial Participation in 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 P6-05-12.