BREAST CANCER—LOCAL/REGIONAL/ADJUVANT 500 Oral Abstract Session Outcome of patients with an ultralow risk 70-gene signature in the MINDACT trial. Josephine Lopes Cardozo, Caroline Drukker, Marjanka Schmidt, Laura van ’t Veer, Annuska Glas, Anke Witteveen, Fatima Cardoso, Martine J. Piccart-Gebhart, Coralie Poncet, Emiel J. Rutgers; Netherlands Cancer Institute, Amsterdam, Netherlands; Amsterdam University Medical Center, Amsterdam, Nether- lands; Agendia, and The University of California San Francisco, San Francsico, CA; Agendia NV, Am- sterdam, Netherlands; Agendia, Amsterdam, Netherlands; Champalimaud Clinical Center/ Champalimaud Foundation, Breast Unit, Lisbon, Portugal; Institut Jules Bordet, Universite� Libre de Bruxelles, Brussels, Belgium; EORTC Headquarters, Brussels, Belgium Background: Gene signatures have proven successful in identifying patients with a low risk of distant re- currence who could forego chemotherapy (CT) and are currently included in international treatment guidelines for breast cancer. For the 70-gene signature (MammaPrint) an additional threshold was es- tablished within the low risk category to identify patients with an ultralow risk of distant recurrence. In independent cohorts, these patients had excellent breast cancer specific survival at 15 years, suggest- ing that ultralow risk cancers represent indolent disease (Esserman, JAMA Oncol 2017, Delahaye, BC Res Treat 2017). Here we evaluate survival of patients with an ultralow risk 70-gene signature who par- ticipated in the randomized phase 3 MINDACT trial (Piccart, Lancet Oncol 2021). Methods: Of the 6,693 patients enrolled in the MINDACT trial (EORTC 10041/BIG 3-04) between 2007-2011, profil- ing revealed an ultralow risk 70-gene signature in 1,000 patients (15%). We assessed 5- and 8-year dis- tant metastasis free interval (DMFI) and breast cancer specific survival (BCSS) in patients stratified by 70-gene signature result (high, low, ultralow), and within the ultralow risk group stratified by clinical risk. For these exploratory analyses, we used Kaplan-Meier estimates for time to event endpoints and Cox-regression models to calculate hazard ratio’s (HR). Results: Median follow-up was 8.7 years. Among the ultralow risk patients (n = 1,000), 67% were $50 years, 81% had tumors < 2cm, 80% were lymph node negative, 96% had grade 1 or 2 tumors and 99% were ER-positive. Systemic therapy was received by 83% of patients (69% endocrine therapy (ET), 14% ET + CT) and 16% received no adjuvant system- ic treatment (AST). Survival estimates for all endpoints are shown in the table; 8-year DMFI was 97.0% (95% CI 95.8-98.1) for ultralow risk. The 8-year DMFI in ultralow risk patients who received no AST or ET only was 97.8% (95% CI 95.3-100) and 97.4% (95% CI 96.1-98.7), respectively. The HR for DMFI was 0.66 (95% CI 0.46-0.95) for ultralow vs low risk, after adjusting for tumor and treatment characteristics (preliminary results). Conclusions: In this prospective study, patients with an ultralow risk 70-gene signature have an excellent prognosis with 8-year BCSS above 99% regardless of clinical risk status, and with an 8-year DMFI of 95-98%. Research Sponsor: This research was supported by a grant from the EORTC Breast Group and from the Netherlands Cancer Institute. Events 5-year DMFI 8-year DMFI 8-year BCSS 70-gene signature (N) (95% CI) (95% CI) (95% CI) Ultralow risk (n = 1000) 36 98.1% (97.2-99.0) 97.0% (95.8-98.1) 99.6% (99.1-100) Low risk* (n = 3295) 192 97.5% (97.0-98.1) 94.5% (93.6-95.3) 98.2% (97.7-98.7) High risk (n = 2398) 273 92.5% (91.4-93.6) 89.2% (87.9-90.5) 93.7% (92.6-94.7) Ultralow risk Clinical low risk (n = 741) 21 98.7% (97.8-99.5) 97.6% (96.4-98.8) 99.7% (99.3-100) Clinical high risk (n = 259) 15 96.3% (94.0-98.7) 95.0% (92.3-97.8) 99.2% (98.0-100) *Low risk excludes ultralow risk. © 2021 by American Society of Clinical Oncology. Visit abstracts.asco.org and search by abstract for disclosure information. BREAST CANCER—LOCAL/REGIONAL/ADJUVANT 501 Oral Abstract Session Breast Cancer Index (BCI) and prediction of benefit from extended aromatase inhibitor (AI) therapy (tx) in HR+ breast cancer: NRG oncology/NSABP B-42. Eleftherios P. Mamounas, Hanna Bandos, Priya Rastogi, Yi Zhang, Kai Treuner, Peter C. Lucas, Charles E. Geyer, Louis Fehrenbacher, Mark Graham, Stephen K. L. Chia, Adam Brufsky, Janice Maria Walshe, Gamini S. Soori, Shaker R. Dakhil, Soonmyung Paik, Sandra M. Swain, Dennis Sgroi, Catherine A. Schnabel, Norman Wolmark; NSABP/NRG Oncology, and The Orlando Health Cancer Insti- tute, Orlando, FL; NSABP/NRG Oncology, and The University of Pittsburgh, Pittsburgh, PA; NSABP/ NRG Oncology and the UPMC Hillman Cancer Center, Pittsburgh, PA; Biotheranostics, San Diego, CA; NSABP/NRG Oncology, and The UPMC Hillman Cancer Center, Pittsburgh, PA; NSABP/NRG Oncology, and Houston Methodist Cancer Center, Houston, TX; NSABP/NRG Oncology, and Kaiser Permanente Oncology Clinical Trials Northern California, Novato, CA; NSABP/NRG Oncology, and Waverly Hematol- ogy Oncology, Cary, NC; NSABP/NRG Oncology, and British Columbia Cancer Agency, Vancouver, BC, Canada; NSABP/NRG Oncology, and University of Pittsburgh, Magee Women’s Hospital, UPMC Hill- man Cancer Center, Pittsburgh, PA; NSABP/NRG Oncology, and Cancer Trials Ireland, St Vincent’s Uni- versity Hospital, Dublin, Ireland; NSABP/NRG Oncology, and Florida Cancer Specialists/Missouri Valley Cancer Consortium, Fort Myers, FL; NSABP/NRG Oncology, and Wichita NCORP via Christi Reg. Med. Ctr, Wichita, KS; NRG Oncology/NSABP, and the Yonsei University College of Medicine, Seoul, South Korea; NSABP/NRG Oncology, and the Georgetown Lombardi Comprehensive Cancer Center, George- town University Medical Center, Washington, DC; Massachusetts General Hospital, Boston, MA Background: The BCI HOXB13/IL17BR ratio (BCI-H/I) has been shown to predict endocrine tx (ET) and extended ET (EET) benefit. We examined the effect of BCI-H/I for EET benefit prediction in NSABP B- 42, evaluating extended letrozole tx (ELT) in HR+ breast cancer patients (pts) who completed 5 yrs of ET. Methods: All pts with available primary tumor tissue were eligible. Primary endpoint was recurrence- free interval (RFI). Secondary endpoints were distant recurrence (DR), breast cancer-free interval (BCFI), and disease-free survival (DFS). Stratified Cox proportional hazards model was used. Due to a non-proportional effect of ELT on DR, time-dependent secondary analyses (#4y, >4y) were performed. Likelihood ratio test evaluated treatment by BCI-H/I interaction. Results: In 2,179 pts analyzed (60% N0; 62% AI only; 80% HER2-), 45% were BCI-H/I-High and 55% BCI-H/I-Low. ELT showed an abso- lute 10y benefit of 1.6% for RFI (HR=0.77, 95% CI 0.57-1.05, p=0.10) (BCI-H/I-Low: 1.1% [HR=0.69, 0.43-1.11, p=0.13]; BCI-H/I-High: 2.4% [HR=0.83, 0.55-1.26, p=0.38]; interaction p=0.55). There was no statistically significant ELT by BCI-H/I interaction for BCFI (BCI-H/I-Low: HR=0.53, 0.36-0.78, p=0.001; BCI-H/I-High: HR=0.85, 0.60-1.21, p=0.36; interaction p=0.07) or for DFS (BCI-H/I-Low: HR=0.75, 0.58-0.95, p=0.017; BCI-H/I-High: HR=0.81, 0.64-1.04, p=0.09; interaction p=0.62). Before 4y, there was no statistically significant ELT benefit on DR in either BCI-H/I group. After 4y, BCI-H/I-High pts had statistically significant ELT benefit on DR (HR: 0.29, 0.12-0.69, p=0.003), while BCI-H/I-Low pts were less likely to benefit (HR: 0.68, 0.33-1.39, p=0.28) (interaction p=0.14). Conclusions: BCI-H/I prediction of ELT benefit on RFI was not confirmed. In time-dependent DR analyses, BCI-H/I-High pts had statistically significant benefit from ELT after 4y, while BCI-H/I-Low pts did not. Observed ELT benefit on BCFI in BCI-H/I-Low pts was primarily driven by second primary breast cancers. Additional follow-up is needed to further characterize BCI-H/I predictive ability in this study. Support: U10CA180868, -180822, U24CA196067; Novartis; Biotheranostics. Clinical trial information: NCT00382070. Research Sponsor: U.S. National Institutes of Health, Pharmaceutical/ Biotech Company. # 4 y > 4 y 4y abs. 10y abs. BCI-H/I HR (95%CI) benefit (%) P HR (95%CI) benefit (%) P All All 0.85 (0.51, 1.43) 0.4 0.55 0.47 (0.28, 0.81) 1.7 0.005 L 0.47 (0.19, 1.17) 1.1 0.10 0.68 (0.33, 1.39) 0.4 0.28 H 1.21 (0.63, 2.32) -0.4 0.56 0.29 (0.12, 0.69) 3.6 0.003 N0 L 0.28 (0.03, 2.48) 0.7 0.22 1.05 (0.35, 3.14) -1.0 0.93 H 2.03 (0.62, 6.60) -1.5 0.23 0.32 (0.06, 1.68) 1.8 0.16 N+ L 0.54 (0.19, 1.48) 2.4 0.22 0.49 (0.19, 1.28) 3.5 0.14 H 0.94 (0.42, 2.09) 0.5 0.87 0.28 (0.10, 0.77) 5.6 0.009 AI Only L 0.50 (0.15, 1.70) 0.8 0.26 0.70 (0.29, 1.68) 0.6 0.42 H 1.06 (0.48, 2.37) 0.2 0.89 0.42 (0.15, 1.19) 3.2 0.09 Tam-AI L 0.44 (0.11, 1.70) 1.7 0.22 0.63 (0.18, 2.24) 0.1 0.47 H 1.56 (0.51, 4.76) -1.5 0.43 0.16 (0.04, 0.76) 4.3 0.009 © 2021 by American Society of Clinical Oncology.