Paluch–Shimon, Shani

Abstract Background Young age is a known risk factor for breast cancer recurrence and mortality, particularly in hormone receptor-positive disease. However, no specific evidence exists on whether age at diagnosis influences clinical behavior and outcomes among carriers of germline BRCA pathogenic or likely pathogenic variants (PVs). Methods The BRCA BCY Collaboration (NCT03673306) is an international, multicenter, hospital-based, retrospective cohort study including women with germline BRCA1 and/or BRCA2 PVs and diagnosed with stage I-III breast cancer at the age of 40 years or younger between January 2000 and December 2020. The present analysis aimed to evaluate clinical features and outcomes of breast cancer in young BRCA carriers according to age at diagnosis, by comparing patients aged ≤30 years with those aged 31-35 and 36-40 years at breast cancer diagnosis. The primary endpoint was disease-free survival (DFS). Overall survival (OS) was a secondary endpoint. Multivariable Cox proportional hazards models were used to estimate adjusted hazard ratios (aHRs), adjusting for risk-reducing mastectomy (RRM) and risk-reducing salpingo-oophorectomy (RRSO) (time-dependent), and stratifying by country, year of diagnosis, tumor size, nodal involvement, tumor grade and hormone receptor status. Results From 109 centers in 5 continents, 5350 young BRCA carriers were included, of whom 1106 (20.7%) were ≤30 years of age, 1945 (36.4%) were 31-35 years and 2299 (43.0%) were 36-40 years at the time of breast cancer diagnosis. Compared to patients aged 31-35 and 36-40 years, those aged ≤30 years were more likely to harbor BRCA1 PVs (71.3%, 62.4%, 61.1%, respectively), to present with high-grade (G3 in 71.3%, 66.6%, 65.0%, respectively), triple-negative breast cancer (56.3%, 48.1%, 46.6%, respectively), and less frequently smaller tumor size (T1: 31.7%, 36.6% and 39.5%, respectively). Consequently, chemotherapy was administered more frequently among patients aged ≤30 years (94.4%, 92.6%, 89.7%, respectively). At a median follow-up of 8.2 years (IQR, 4.7-12.8), 8-year DFS rate was 65.0% among patients aged ≤30 years, 64.7% in the 31-35 years group, and 65.8% in the 36-40 years group. No significant association between age at diagnosis and DFS outcome was observed (31-35 vs. ≤30 years: aHR 1.03, 95% CI 0.89-1.19; 36-40 vs. ≤30 years aHR 1.00, 95% CI 0.87-1.16). Similarly, no significant association between age at diagnosis and OS was observed (31-35 vs. ≤30 years: aHR 1.10, 95% CI 0.86-1.41; 36-40 vs. ≤30 years: aHR 1.11, 95% CI 0.87-1.43). Subgroup analyses by specific BRCA gene, tumor subtype, tumor size, nodal status, and chemotherapy use revealed no statistically significant interaction with age at diagnosis in terms of DFS or OS (all p for interaction > 0.05). Specifically, no significant differences between age groups were observed among patients with luminal-like tumors for both DFS and OS. Conclusions In this unique international cohort of BRCA carriers diagnosed with breast cancer at a young age (≤40 years), we found no significant differences in DFS nor OS across different age groups. Notably, very young age (≤30 years) at diagnosis was not associated with worse outcomes compared to 31-35 years or 36-40 years. Age per se should not be considered a negative prognostic factor in BRCA carriers when appropriate treatment is provided. Citation Format: E. Blondeaux, A. Meacci, M. Fragío Gil, E. Klocker, F. Coussy, H. Kim, R. Bernstein Molho, F. Hilbers, A. Di Meglio, A. Kwong, K. Pogoda, J. Bajpai, H. Wildiers, E. Agostinetto, J. Balmana, H. C. Moore, K. Phillips, A. H. Partridge, C. Rousset-Jablonski, F. A. Peccatori, A. Toss, T. Renaud, C. Anghelone, A. Benitez Cruz, S. Paluch-Shimon, J. Lee, R. Fruscio, W. Cui, S. M. Wong, M. Lee, M. Rozenblit, C. Vernieri, C. Villarreal-Garza, A. Matikas, M. Dieci, L. De Marchis, J. K. Plichta, K. J. Ruddy, D. Can Guven, F. Puglisi, Z. Kemp, P. A. Meireles, L. Del Mastro, V. Delucchi, M. Lambertini. Association between age at diagnosis and survival among young BRCA carriers with breast cancer: results from an international multicenter hospital-based cohort study [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PD4-07.

Abstract Background: Young BRCA carriers may undergo breast conserving surgery (BCS) or mastectomy with or without contralateral risk reducing mastectomy at the time of an index breast cancer diagnosis. A variety of factors may influence surgical decision making. Methods: The BRCA BCY Collaboration (NCT03673306) is an international, hospital-based, retrospective cohort study conducted at 109 centres across 5 continents including women with germline pathogenic or likely pathogenic variants (PV) in BRCA1/2 diagnosed between 2000 and 2020 with invasive stage I-III breast cancer prior to or at age 40 years. The primary objective of the present analysis was to evaluate surgical management in these patients. Breast surgery was defined as BCS, unilateral mastectomy, or bilateral mastectomy administered as part of primary treatment for a first diagnosis of invasive breast cancer. Multivariable logistic regression was used to determine factors associated with receipt of bilateral mastectomy. Results: Of 5660 eligible BRCA1/2 carriers, 4715 had unilateral stage I-III breast cancer with surgical treatment details available. The median age of the cohort was 35 years (IQR, 31-38 years). Overall, 1805 (38.3%) patients underwent BCS, 1752 (37.2%) underwent unilateral mastectomy, and 1158 (24.6%) underwent bilateral mastectomy. The proportion of young BRCA1/2 carriers undergoing BCS decreased over the study period (55.7% in 2000 vs. 27.0% in 2020), whereas the use of bilateral mastectomy significantly increased (8.0% in 2000 vs. 44.4% in 2020). Bilateral mastectomy was more common in women who had genetic testing performed before (57.0%) or within 6 months of a breast cancer diagnosis (38.5%), compared to those tested after diagnosis (5.1%, p<0.001). On multivariable analysis, compared to those tested after diagnosis, earlier genetic testing remained the strongest predictor of bilateral mastectomy receipt (testing prior to diagnosis: OR 20.7 [95% CI 15.3-28.1]; testing at diagnosis: OR 6.8 [95% CI 5.4-8.7]). Other predictors of bilateral mastectomy receipt included geographic region, later year of diagnosis, smaller tumor size, node negative disease, and neoadjuvant treatment. In subgroup analysis including 2327 patients who had genetic testing performed before or within 6 months of diagnosis, 42.0% underwent bilateral mastectomy, with the lowest rates reported in Asia/Africa (26.1%) and the highest rates reported in North America (66.4%, p<0.001). In adjusted subgroup analyses, BRCA1 PV, later year of diagnosis, smaller tumor size, node negative disease, neoadjuvant treatment, and geographic region remained independently associated with bilateral mastectomy. Conclusions: In this large, international study of young affected BRCA carriers, geographic region and timing of genetic testing strongly impacted surgical management. These data support early genetic testing for young women with breast cancer to help optimize local therapy decisions. Citation Format: S. M. Wong, E. Blondeaux, V. Delucchi, F. Coussy, R. Bernstein Molho, S. Linn, A. Di Meglio, A. Kwong, K. Pogoda, E. Agostinetto, I. Nevelsteen, J. Balmana, H. C. Moore, A. Toss, A. Ferrari, C. Rousset-Jablonski, T. Renaud, K. Phillips, F. A. PeccatorI, M. Agustina Ipina, S. Paluch-Shimon, J. Ryu, W. Kui, M. Lee, R. Fruscio, M. Rozenblit, C. Vernieri, A. Matikas, M. Dieci, F. J. Couch, L. De Marchis, S. E. Hwang, D. Aguilar-y Mendez, D. Can Guven, M. Swain, C. Gianni, S. Spinaci, G. Montagna, M. Lambertini, H. Kim. Surgical management of young BRCA1/2 carriers with early onset breast cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PD12-01.

PURPOSE To investigate the clinical behavior of breast cancer in young BRCA carriers according to the specific BRCA gene ( BRCA1 v BRCA2 ) and the association of the timing of genetic testing (before v at diagnosis) with prognosis. METHODS This was an international, multicenter, hospital-based, retrospective cohort study that included 4,752 patients harboring germline pathogenic/likely pathogenic variants (PVs) in BRCA1 or BRCA2 , who were diagnosed with stage I-III invasive breast cancer at 40 years or younger between January 2000 and December 2020 in 78 centers worldwide (ClinicalTrials.gov identifier: NCT03673306 ). RESULTS Compared with BRCA2 carriers (n = 1,683), BRCA1 carriers (n = 3,069) had more frequently hormone receptor–negative (74.4% v 15.5%) and high-grade (77.5% v 49.1%) tumors. Similar outcomes were observed in BRCA1 and BRCA2 carriers but with a different pattern and risk of disease-free survival events over time. Compared with patients tested for BRCA at diagnosis (ie, between 2 months before and up to 6 months after diagnosis; n = 1,671), those tested before diagnosis (ie, any time up to 2 months before diagnosis; n = 411) had smaller tumors (T1: 61.3% v 32.4%), less nodal involvement (N0: 65.9% v 50.8%), less frequently received chemotherapy (84.4% v 92.9%), and axillary dissection (37.5% v 47.4%). Patients tested before diagnosis had better overall survival (OS; unadjusted hazard ratio [HR], 0.61 [95% CI, 0.40 to 0.92]); however, this result lost statistical significance after adjustment for potential confounders including tumor stage (adjusted HR, 0.74 [95% CI, 0.47 to 1.15]). CONCLUSION This global study provides evidence on the different clinical behavior of breast cancer in young BRCA1 and BRCA2 carriers. Identifying a BRCA PV in healthy individuals was associated with earlier-stage breast cancer diagnosis and lower treatment burden, as well as better unadjusted OS.

Abstract Background: Oncofertility counseling in BRCA carriers has unique challenges due to a possible negative impact of germline pathogenic/likely pathogenic variants (PVs) on reproductive potential and the indication to undergo risk-reducing bilateral salpingo-oophorectomy. While previous studies demonstrated the safety of pregnancy in women with prior breast cancer (BC) history, limited evidence exists in BRCA carriers specifically. We report the results of the largest study to date investigating likelihood of pregnancy after BC, reproductive and disease outcomes specifically in BRCA carriers. Methods: This was an international, multicenter, hospital-based, retrospective cohort study including young BRCA carriers with history of BC (NCT03673306). Eligible patients were women harboring germline PVs in BRCA1 and/or BRCA2 and diagnosed with stage I-III invasive BC at the age of ≤ 40 years between January 2000 and December 2020. BRCA healthy carriers or patients with BRCA variants of unknown significance, non-invasive BC, lack of follow-up, prior ovarian cancer or other malignancies without history of BC were excluded. Primary endpoints were pregnancy rate and disease-free survival (DFS). Overall survival (OS), BC specific survival (BCSS), pregnancy, fetal and obstetric outcomes were secondary endpoints. To mitigate the impact of guaranteed time bias, two survival analyses were performed: 1) Extended Cox model with occurrence of pregnancy as a time-varying covariate; 2) Case-control analysis by matching 1:3 patients with and without a pregnancy for type of BRCA PV, hormone receptor status, nodal status and year at diagnosis; moreover, each control had to have a disease-free interval longer than the time occurring between BC diagnosis and conception of the matched case. Results: From 78 centers worldwide, 4,732 patients were included, of whom 659 had at least one pregnancy after BC (pregnancy cohort) and 4,073 did not (non-pregnancy cohort). Patients in the pregnancy cohort were significantly more likely to carry BRCA1 PVs, to be younger at BC diagnosis, to have node-negative and hormone receptor-negative (HR-) BC (all p< 0.01). Pregnancy rate at 10 years was 22% (95% CI 21%-24%) overall, 18% (95% CI 16%-21%) and 26% (95% CI 24%-26%) in patients with HR+ and HR- BC, respectively (p< 0.01). Median time from BC diagnosis to conception was 3.5 years (IQR 2.2-5.3 years), significantly longer in patients with HR+ than HR- BC (4.3 vs 3.2 years, p< 0.01). Among 659 patients with a pregnancy after BC, 45 (6.8%) and 63 (9.6%) experienced an induced abortion or a miscarriage, respectively. Of the 517 (78.5%) patients with completed pregnancy, 54 (10.4%) had twins and 406 (78.5%) delivered at term (delivery ≥37 weeks). Among the 571 babies born, 5 (0.9%) had congenital anomalies. Median follow-up was 7.8 years (IQR, 4.5-12.6 years). No significant difference in DFS was observed between the pregnancy and non-pregnancy cohorts (unadjusted HR 0.97, 95% CI 0.82-1.15, p=0.74; adjusted HR [aHR] 0.99, 95% CI 0.81-1.20, p=0.90). Patients in the pregnancy cohort showed significantly better BCSS (HR 0.53, 95% CI 0.38-0.74, p< 0.01; aHR 0.59, 95% CI 0.41-0.86, p< 0.01) and OS (HR 0.52, 95% CI 0.38-0.72, p< 0.01; aHR 0.58, 95% CI 0.40-0.85, p< 0.01). Similar results were obtained in the case-control analysis. Subgroup analyses of survival endpoints according to patient, tumor and treatment characteristics will be presented at the conference. Conclusions: In this global study, 1 out of 5 young BRCA carriers conceived within 10 years after a BC diagnosis, higher than rates previously reported in unselected young BC populations. Pregnancy following BC in BRCA carriers did not appear to adversely impact maternal prognosis or fetal outcomes. These findings should be incorporated into oncofertility counseling of young BRCA carriers with BC. Citation Format: Matteo Lambertini, Eva Blondeaux, Elisa Agostinetto, Anne-Sophie Hamy-Petit, Hee Jeong Kim, Camila Chiodi, Rinat Bernstein-Molho, Florentine Hilbers, Katarzyna Pogoda, Estela Carrasco Lopez, Kevin Punie, Jyoti Bajpai, Michail Ignatiadis, Halle Moore, Kelly-Anne Phillips, Angela Toss, Christine Rousset-Jablonski, Fedro Alessandro Peccatori, Tiphaine Renaud, Alberta Ferrari, Shani Paluch-Shimon, Robert Fruscio, Wanda Cui, Stephanie Wong, Claudio Vernieri, Kathryn Ruddy, Maria Vittoria Dieci, Alexios Matikas, Mariya Rozenblit, Cynthia Villareal Garza, Laura De Marchis, Lucia Del Mastro, Fabio Puglisi, Maria Del Pilar Estevez-Diz, Kenny A. Rodriguez-Wallberg, Bela Mrinakova, Sarah Meister, Luca Livraghi, Florian Clatot, Rinat Yerushalmi, Carmine De Angelis, Rodrigo Sánchez-Bayona, Icro Meattini, Natalia Cichowska-Cwalińska, Martine Berlière, Mahmoud Salama, Ugo De Giorgi, Amir Sonnenblick, Hatem Azim, Ann Partridge. Pregnancy after breast cancer in young women with germline BRCA pathogenic variants: results from an international cohort study [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 GS02-13.

Abstract Background: Abemaciclib is approved both for high-risk early breast cancer as well as advanced breast cancer (ABC) in the first- and second-line setting. In MONARCH 2, the addition of abemaciclib to fulvestrant significantly improved both progression-free survival (PFS) and overall survival (OS) in patients with HR+, HER2- ABC with disease progression on prior endocrine therapy (ET). In MONARCH 3, the addition of abemaciclib to a nonsteroidal aromatase inhibitor (NSAI) significantly improved PFS (HR, 0.540; 95% CI, 0.418-0.698; p=0.000002) as initial therapy in HR+, HER2- ABC. At the last interim OS analysis (~252 events, at 5.8 years follow-up [FU]), a numerically favorable median OS difference (12.6 months) was observed (HR, 0.754; 95% CI, 0.584-0.974; p=0.0301, non-significant [NS]). Here, we present the final OS analysis of MONARCH 3 (NCT02246621). Methods: MONARCH 3 is a randomized, double-blind, Phase 3 study of abemaciclib + NSAI (anastrozole or letrozole) vs placebo + NSAI in postmenopausal women with HR+, HER2- ABC without prior systemic therapy in the advanced setting. OS was a gated secondary endpoint and chemotherapy-free survival (CFS) an exploratory endpoint. Final OS analysis was planned after approximately 315 OS events had occurred in the intent-to-treat (ITT) population with a split alpha between the ITT population and the subgroup with visceral disease (sVD) according to a prespecified graphical testing scheme. Kaplan-Meier method and stratified Cox proportional hazards models were used for time-to-event analyses. All reported p-values are two-sided. Results A total of 493 women were randomized 2:1 to receive abemaciclib + NSAI (n=328) or placebo + NSAI (n=165). After a median FU of 8.1 years, 7% of patients were still receiving treatment in the abemaciclib arm vs 3% in the placebo arm. In the ITT population, 314 OS events were observed (198 deaths among 328 patients [60%] in the abemaciclib arm and 116 among 165 [70%] in the placebo arm; HR, 0.804; 95% CI, 0.637-1.015; p=0.0664, NS). Median OS was 66.8 months in the abemaciclib arm and 53.7 months in the placebo arm, a numerical difference of 13.1 months in the ITT population. In the sVD, 178 events were observed (113 deaths among 173 patients [65%] in the abemaciclib arm and 65 among 90 [72%] in the placebo arm; HR, 0.758; 95% CI, 0.558-1.030; p=0.0757, NS). Median OS was 63.7 months in the abemaciclib arm and 48.8 months in the placebo arm, a numerical difference of 14.9 months in the sVD. Consistent OS differences were observed across prespecified subgroups. PFS benefit was sustained (median 29.0 vs 14.8 months; HR, 0.535; 95% CI, 0.429-0.668; nominal p<0.0001) with substantial difference in 6-year PFS rates (23.3% vs 4.3% for abemaciclib vs placebo). CFS was also improved with abemaciclib vs placebo (median 46.7 vs 30.6 months; HR, 0.693; 95% CI, 0.557-0.863; nominal p=0.0010). No new safety signals were observed with longer term use. Conclusion In patients with HR+, HER2- ABC, abemaciclib in combination with a NSAI resulted in numerically longer OS compared to NSAI alone; however, statistical significance was not reached after a median FU of 8.1 years. The clinically meaningful improvement in median OS (>13 months) combined with the sustained significant improvement in median PFS (>14 months) and substantial extension in median CFS (>16 months) continue to support the use of abemaciclib in combination with NSAI as first-line therapy in ABC. Citation Format: Matthew Goetz, Masakazu Toi, Jens Huober, Joo Hyuk Sohn, Olivier Trédan, Inhae Park, Mario Campone, Shin-Cheh Chen, Luis Manual Manso, Shani Paluch-Shimon, Orit C. Freedman, Valerie Andre, Abhijoy Saha, Gertjan van Hal, Ashwin Shahir, Hiroji Iwata, Stephen RD Johnston, Joyce O'Shaughnessy, Xavier Pivot, Sara Tolaney, Sara Hurvitz, Antonio Llombart. MONARCH 3: Final overall survival results of abemaciclib plus a nonsteroidal aromatase inhibitor as first-line therapy for HR+, HER2- advanced breast cancer [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 GS01-12.

ImportanceYoung women with breast cancer who have germline pathogenic variants in BRCA1 or BRCA2 face unique challenges regarding fertility. Previous studies demonstrating the feasibility and safety of pregnancy in breast cancer survivors included limited data regarding BRCA carriers.ObjectiveTo investigate cumulative incidence of pregnancy and disease-free survival in young women who are BRCA carriers.Design, Setting, and ParticipantsInternational, multicenter, hospital-based, retrospective cohort study conducted at 78 participating centers worldwide. The study included female participants diagnosed with invasive breast cancer at age 40 years or younger between January 2000 and December 2020 carrying germline pathogenic variants in BRCA1 and/or BRCA2. Last delivery was October 7, 2022; last follow-up was February 20, 2023.ExposurePregnancy after breast cancer.Main Outcomes and MeasuresPrimary end points were cumulative incidence of pregnancy after breast cancer and disease-free survival. Secondary end points were breast cancer–specific survival, overall survival, pregnancy, and fetal and obstetric outcomes.ResultsOf 4732 BRCA carriers included, 659 had at least 1 pregnancy after breast cancer and 4073 did not. Median age at diagnosis in the overall cohort was 35 years (IQR, 31-38 years). Cumulative incidence of pregnancy at 10 years was 22% (95% CI, 21%-24%), with a median time from breast cancer diagnosis to conception of 3.5 years (IQR, 2.2-5.3 years). Among the 659 patients who had a pregnancy, 45 (6.9%) and 63 (9.7%) had an induced abortion or a miscarriage, respectively. Of the 517 patients (79.7%) with a completed pregnancy, 406 (91.0%) delivered at term (≥37 weeks) and 54 (10.4%) had twins. Among the 470 infants born with known information on pregnancy complications, 4 (0.9%) had documented congenital anomalies. Median follow-up was 7.8 years (IQR, 4.5-12.6 years). No significant difference in disease-free survival was observed between patients with or without a pregnancy after breast cancer (adjusted hazard ratio, 0.99; 95% CI, 0.81-1.20). Patients who had a pregnancy had significantly better breast cancer–specific survival and overall survival.Conclusions and RelevanceIn this global study, 1 in 5 young BRCA carriers conceived within 10 years after breast cancer diagnosis. Pregnancy following breast cancer in BRCA carriers was not associated with decreased disease-free survival.Trial RegistrationClinicalTrials.gov Identifier: NCT03673306

Background: Abemaciclib is the first and only cyclin-dependent kinases 4 and 6 inhibitor approved for adjuvant treatment of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2−), node-positive, and high-risk early breast cancer (EBC), with indications varying by geography. Premenopausal patients with HR+, HER2− tumors may have different tumor biology and treatment response compared to postmenopausal patients. Objectives: We describe the efficacy and safety of abemaciclib plus endocrine therapy (ET) for the large subgroup of premenopausal patients with HR+, HER2− EBC in monarchE. Design: Randomized patients (1:1) received adjuvant ET with or without abemaciclib for 2 years plus at least 3 additional years of ET as clinically indicated. Methods: Patients were stratified by menopausal status (premenopausal versus postmenopausal) at diagnosis. Standard ET (tamoxifen or aromatase inhibitor) with or without gonadotropin-releasing hormone agonist was determined by physician’s choice. Invasive disease-free survival (IDFS) and distant relapse-free survival (DRFS) by menopausal status were assessed at data cutoff on 1 April 2021 (median follow-up of 27 months). Results: Among randomized patients, 2451 (43.5%) were premenopausal and 3181 (56.4%) were postmenopausal. The choice of ET for premenopausal patients varied considerably between countries. Treatment benefit was consistent across menopausal status, with a numerically greater effect size in premenopausal patients. For premenopausal patients, abemaciclib with ET resulted in a 42.2% and 40.3% reduction in the risk of developing IDFS and DRFS events, respectively. Absolute improvement at 3 years was 5.7% for IDFS and 4.4% for DRFS rates. Safety profile for premenopausal patients was consistent with the overall safety population. Conclusion: Abemaciclib with ET demonstrated clinically meaningful treatment benefit for IDFS and DRFS versus ET alone regardless of menopausal status and first ET, with a numerically greater benefit in the premenopausal compared to the postmenopausal population. Safety data in premenopausal patients are consistent with the overall safety profile of abemaciclib.

Purpose Abemaciclib, a cyclin-dependent kinase 4 and 6 inhibitor, demonstrated efficacy as monotherapy and in combination with fulvestrant in women with hormone receptor (HR)–positive, human epidermal growth factor receptor 2 (HER2)–negative advanced breast cancer previously treated with endocrine therapy. Methods MONARCH 3 is a double-blind, randomized phase III study of abemaciclib or placebo plus a nonsteroidal aromatase inhibitor in 493 postmenopausal women with HR-positive, HER2-negative advanced breast cancer who had no prior systemic therapy in the advanced setting. Patients received abemaciclib or placebo (150 mg twice daily continuous schedule) plus either 1 mg anastrozole or 2.5 mg letrozole, daily. The primary objective was investigator-assessed progression-free survival. Secondary objectives included response evaluation and safety. A planned interim analysis occurred after 189 events. Results Median progression-free survival was significantly prolonged in the abemaciclib arm (hazard ratio, 0.54; 95% CI, 0.41 to 0.72; P = .000021; median: not reached in the abemaciclib arm, 14.7 months in the placebo arm). In patients with measurable disease, the objective response rate was 59% in the abemaciclib arm and 44% in the placebo arm ( P = .004). In the abemaciclib arm, diarrhea was the most frequent adverse effect (81.3%) but was mainly grade 1 (44.6%). Comparing abemaciclib and placebo, the most frequent grade 3 or 4 adverse events were neutropenia (21.1% v 1.2%), diarrhea (9.5% v 1.2%), and leukopenia (7.6% v 0.6%). Conclusion Abemaciclib plus a nonsteroidal aromatase inhibitor was effective as initial therapy, significantly improving progression-free survival and objective response rate and demonstrating a tolerable safety profile in women with HR-positive, HER2-negative advanced breast cancer.