Standard Adjuvant Endocrine Therapy Research Articles

Baseline (BL) characteristics and efficacy endpoints for patients (pts) with node-negative (N0) HR+/HER2− early breast cancer (EBC): NATALEE trial.

512 Background: NATALEE assessed ribociclib (RIB) + non-steroidal aromatase inhibitor (NSAI) vs NSAI alone in pts with HR+/HER2− EBC at increased risk of recurrence, including pts with N0 disease, and showed a statistically significant invasive disease-free survival (iDFS) benefit. We report BL characteristics, efficacy, and safety for the N0 subgroup. Methods: Pts with stage II/III HR+/HER2− EBC were randomized (R) 1:1 to RIB 400 mg/d (3 wk on/1 wk off for 36 mo) + NSAI (letrozole or anastrozole for ≥60 mo) or NSAI alone. Men and premenopausal women received goserelin. Pts could receive any standard (neo)adjuvant endocrine therapy (ET) ≤12 mo before randomization. In the intent-to-treat (ITT) population, 78% of pts completed 3y of RIB treatment (tx) or discontinued early with 21% still on tx at the time of this analysis (data cutoff: July 21, 2023; median follow up, 33 mo). The N0 subgroup included pts with T2N0 (stage IIA; with grade [G]3, or G2 disease and Ki-67 ≥20% or high genomic risk [HGR]), T3N0 (stage IIB), and T4N0 (stage IIIB); T1N0 was excluded. Results: Of 2549 pts R to RIB + NSAI and 2552 to NSAI alone, 285 (11%) and 328 (13%) had N0 disease, respectively. BL characteristics for the N0 subgroup were balanced across arms. Most pts were premenopausal (RIB + NSAI: 67% vs NSAI alone: 63%). Pts with N0 disease had anatomic stage IIA (RIB + NSAI: 74% vs NSAI alone: 73%), stage IIB (17% vs 13%), or stage IIIB (9% vs 12%) disease (Table). Most pts received prior chemotherapy (RIB + NSAI: 72% vs NSAI alone: 71%); prior ET was received by 59% vs 62% of pts with RIB + NSAI vs NSAI alone. For pts with T2N0 disease treated with RIB + NSAI vs NSAI alone, 49% vs 45% had G3 disease and 49% vs 53% had G2 disease (54% vs 56% with T2N0, G2 & Ki-67 > 20%; 13% vs 23% with T2N0, G2, Ki-67 ≤20%/missing & HGR). Consistent with the ITT population, RIB + NSAI improved iDFS (HR, 0.72; 95% CI, 0.41-1.27; 3y rate with RIB + NSAI vs NSAI alone, 93.2% vs 90.6%), distant disease–free survival (DDFS; HR, 0.70; 95% CI, 0.38-1.29; 3y rate, 94.3% vs 91.5%), and distant recurrence–free survival (DRFS; HR, 0.58; 95% CI, 0.29-1.17; 3y rate, 96.3% vs 92.5%) in pts with high-risk N0 disease. The safety profile of RIB in the N0 subgroup was consistent with the ITT population. The rate of discontinuation due to all grade adverse events was 24% vs 8% with RIB + NSAI vs NSAI alone. Conclusions: This analysis showed a consistent efficacy benefit and manageable safety profile of RIB + NSAI vs NSAI alone in pts with N0 disease in NATALEE. The 3y iDFS, DDFS, and DRFS rates in the control arm at this early follow-up underscore the risk of recurrence for the N0 subgroup. These findings support the use of RIB in pts with HR+/HER2− EBC at increased risk of recurrence, including pts with N0 disease. Clinical trial information: NCT03701334 . [Table: see text]

Abstract PO2-18-09: A phase 3 randomized open-label study of extended adjuvant therapy with camizestrant vs standard endocrine therapy in patients with ER+/HER2– early breast cancer and an intermediate or high risk of recurrence (CAMBRIA 1)

Abstract Background: Definitive locoregional (surgery ± radiotherapy) and standard adjuvant endocrine therapy (ET) (± chemotherapy or cyclin-dependent kinase 4/6 inhibitor [CDK4/6i]) can achieve cure in many patients (pts) with estrogen receptor-positive/human epidermal growth factor receptor 2-negative (ER+/HER2–) early breast cancer (BC). Nevertheless, a significant proportion of pts with stage I–III disease will experience recurrence to metastatic, incurable disease (5- and 10-year cumulative incidences of recurrence of 8.3% and 14.0%, respectively). There is evidence that incorporating a more effective endocrine therapy after 2 years of standard adjuvant ET can result in clinical benefit for high-risk individuals. Camizestrant is a next-generation oral selective ER degrader and pure ER antagonist. In SERENA-2, camizestrant 75 mg and 150 mg significantly prolonged progression-free survival vs fulvestrant in postmenopausal women with ER+/HER2– advanced BC with disease recurrence or progression after ET. The CAMBRIA-1 study (NCT05774951) is evaluating the potential of extended adjuvant therapy with camizestrant to improve outcomes in pts with ER+/HER2– early BC with an intermediate or high risk of recurrence after definitive locoregional therapy and standard adjuvant ET. Trial design: This phase 3 randomized, open-label study is enrolling women (pre- or postmenopausal) and men with ER+/HER2– (immunohistochemistry 0/1+/2+/in situ hybridization-negative) early BC who have completed definitive locoregional therapy and standard adjuvant ET (± CDK4/6i) for ≥2 and ≤5 years (+ 3 months) without disease recurrence. Pts must be considered at intermediate or high risk of recurrence based on clinical, biological, and genomic factors. Pts are randomized (1:1) to continue standard ET of the investigator’s choice (tamoxifen or aromatase inhibitor ± luteinizing hormone-releasing hormone [LHRH] agonist) or camizestrant ± LHRH agonist for up to 60 months. The primary endpoint is invasive BC-free survival (STEEP 2.0 criteria). Secondary endpoints include invasive disease-free survival and distant relapse-free survival (STEEP 2.0 criteria), overall survival, safety, and health-related quality of life. Primary endpoint analysis will use a stratified log-rank test adjusting for stratification factors, assuming a two-sided significance level of 5%. Approximately 4300 pts will be randomized; enrollment is ongoing. Clinical trial identification: NCT05774951 Editorial acknowledgment: Writing assistance was provided by Alison Lovibond, PhD, of BOLDSCIENCE Inc., funded by AstraZeneca. Legal entity responsible for the study: AstraZeneca Funding: This study was supported by AstraZeneca. Citation Format: Erika Hamilton, Sibylle Loibl, Naoki Niikura, Priya Rastogi, Kamal S. Saini, Ioanna Gioni, Teresa Klinowska, Ingrid A. Mayer, Mary Stuart, Emilia Syta, Andrew Walding, Thomas Bachelot. A phase 3 randomized open-label study of extended adjuvant therapy with camizestrant vs standard endocrine therapy in patients with ER+/HER2– early breast cancer and an intermediate or high risk of recurrence (CAMBRIA 1) [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 PO2-18-09.

Abstract PO1-01-08: The impact of drug-drug interactions between palbociclib and proton pump inhibitors on clinical outcomes of patients with hormone receptor positive, HER2-negative, early breast cancer: an exploratory analysis of the PALLAS study

Abstract Background: Data suggest that concomitant intake of proton pump inhibitors (PPI) may create drug-drug interactions, potentially impacting efficacy of agents including palbociclib, which is widely used in the treatment of metastatic hormone-receptor-positive/HER2-negative (HR+/HER2-) breast cancer. In the open label, randomized, phase 3 PALLAS trial, the addition of palbociclib for two years to standard adjuvant endocrine therapy (ET) in patients with HR+/HER2- early breast cancer (EBC) did not improve invasive disease-free survival (IDFS) compared to adjuvant ET alone. We explored whether concomitant use of PPIs could have affected clinical outcomes in patients treated with palbociclib in PALLAS. Methods: This is an exploratory, unplanned analysis of the PALLAS trial (AFT-05/ABCSG-42/PrE0109/BIG-14-13, NCT02513394), which enrolled 5796 patients with stage II-III HR+/HER2- EBC. Patients were randomized to receive either 2 years of palbociclib (125 mg oral capsules once daily on days 1-21 of a 28-day cycle) with adjuvant ET or ET alone. Primary endpoint was IDFS in the intention-to-treat population. The present exploratory analysis included patients who received at least one dose of palbociclib. Definitions of IDFS, distant relapse-free survival (DRFS) and overall survival (OS) were according to the PALLAS protocol (STEEP criteria), using first day of palbociclib intake as start date. Only PPI concomitant intake during palbociclib treatment was considered. To determine the association of concomitant PPI use with IDFS, DRFS, and OS, uni- and multivariable Cox models with time-dependent PPI (the latter adjusted for age, prior chemotherapy, progesterone receptor, grade, tumor stage, nodal stage, body mass index (BMI)) were used. Also, the association between PPI use and neutropenia was investigated in patients initiating PPI prior to randomization vs never. Odds ratios (OR) unadjusted and adjusted for age and BMI estimated with logistic regression models are reported. Results: Of 2840 patients treated with palbociclib + ET, 533 (18.8%) had concomitant PPI and palbociclib intake. Median duration of PPI intake was 10.8 months (interquartile range 2.3-22.3). Most patients received omeprazole as PPI (n=265, 49.7%). PPI intake was significantly associated with older age, post-menopausal status, use of aromatase inhibitors as ET, higher BMI, and worse ECOG status (all p< 0.001). Concomitant PPI intake was not significantly associated with survival outcomes (Table 1). Unadjusted all grade neutropenia rates were slightly lower in patients who initiated PPI prior study start vs patients never initiating (79% vs 85%, unadjusted OR 0.66, 95%CI 0.50-0.88). After adjustment for BMI and age, the difference between the groups decreased (adjusted OR = 0.77, 95%CI 0.57-1.04). Similar effect sizes were found for grade 3/4 neutropenia rates (54% vs 64%, unadjusted OR 0.66, 95%CI 0.52-0.83, adjusted OR 0.81, 95%CI 0.64-1.03). Conclusions: Our exploratory analysis did not demonstrate a statistically significant relationship between concomitant use of PPIs and palbociclib and survival outcomes of patients in the PALLAS trial. Nonetheless, careful consideration of concomitant medications and of drug-drug interactions is important when studying novel agents in the adjuvant breast cancer setting. Support: AFT, Pfizer; https://acknowledgments.alliancefound.org Table 1. Association between PPI intake and survival outcomes. Citation Format: Elisa Agostinetto, Georg Pfeiler, Dominik Hlauschek, Erica Mayer, Matteo Lambertini, Evandro de Azambuja, Meritxell Bellet- Ezquerra, Jane Meisel, Gabor Rubovszky, Nicholas Zdenkowski, Yelena Novik, Manuel Ruíz - Borrego, Karen Gelmon, Eleftherios Mamounas, Hiroji Iwata, Dongrui Lu, Lidija Sölkner, Christian Fesl, Michael Gnant, Angela DeMichele. The impact of drug-drug interactions between palbociclib and proton pump inhibitors on clinical outcomes of patients with hormone receptor positive, HER2-negative, early breast cancer: an exploratory analysis of the PALLAS 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 PO1-01-08.

Abstract 6520: Clinical verification oftherelationship betweenserum lipid metabolism andtumor immune microenvironment inpostmenopausal hormone receptor-positive/HER2-negative breast cancer patients

Abstract Background: Recently, some basic research has reported that the tumor immune microenvironment (TIME) is related to the therapeutic efficacy and prognosis of breast cancer patients, and that the regulation of metabolism can affect TIME and enhance antitumor immunity. Suppression of aromatase expression from adipose tissue is the standard adjuvant endocrine therapy for postmenopausal hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative breast cancer, but few studies have examined the impact of controlling lipid metabolism on TIME and cancer prognosis. Materials and Methods: Except for patients with ductal carcinoma in situ, 531 postmenopausal HR-positive/HER2-negative breast cancer patients treated with curative surgery between 2011 and 2017 were examined. Serum lipid levels and systemic immune-related markers were evaluated by blood samples, and tumor-infiltrating lymphocytes (TILs) in cancer tissue samples were investigated by immunohistochemistry. We also examined the relationship between lipid metabolism, TIME, and prognosis, respectively. Results: Good serum lipid control group was significantly correlated with low neutrophil- to-lymphocyte ratio (NLR) (p = 0.024) and high TILs (p = 0.039). The median follow-up time for the assessment of prognosis was 5.5 years, and 67 patients had recurrence. Only patients treated with aromatase inhibitor as adjuvant endocrine therapy showed significantly better recurrence-free survival (RFS) in the good lipid control group (p = 0.025, log-rank). Also, multivariate analyses showed that good serum lipid control was an independent prognostic factor for recurrence (HRs = 4.722, 95%CI: 1.006-22.161, p = 0.049). Patients with high CD8/FOXP3 ratio (CFR) had significantly better RFS (p=0.027, log-rank) and tended to have good lipid control. Conclusions: Good control of serum lipid metabolism may inhibit the acquisition of resistance to endocrine therapy by improving TIME and induce favorable outcome in postmenopausal HR-positive/HER2-negative breast cancer patients. Citation Format: Wataru Goto, Hanae Matsuda, Saeko Henmi, Mariko Nishikawa, Asuka Kouchi, Rika Kouhashi, Akimichi Yabumoto, Koji Takada, Yukie Tauchi, Kana Ogisawa, Tamami Morisaki, Shinichiro Kashiwagi. Clinical verification oftherelationship betweenserum lipid metabolism andtumor immune microenvironment inpostmenopausal hormone receptor-positive/HER2-negative breast cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6520.

Comparison of effects of tamoxifen and Toremifene on hepatic function and serum lipids in breast cancer patients during adjuvant endocrine therapy.

To investigate the effects of tamoxifen (TAM) and toremifene (TOR) on hepatic function and serum lipid levels in breast cancer patients receiving adjuvant endocrine therapy. The clinical data of 597 early breast cancer patients treated at the First Affiliated Hospital of Nanjing Medical University between January 2016 and December 2022 were collected. All the patients received standard adjuvant endocrine therapy with TAM or TOR after chemotherapy. Hepatic function and serum lipid data of all patients before and at 6 months and 1, 2, and 3 years after the treatment were collected retrospectively and analyzed statistically. There: no negative effect on hepatic function was observed in patients treated with either TAM or TOR. The triglyceride levels in both groups increased during treatment, and the effect of TAM on improving total cholesterol levels was stronger. Total cholesterol levels were not affected by time or treatment regimen. The low-density lipoprotein cholesterol levels decreased in both groups, and the effect was similar between groups. TAM can decrease the high-density lipoprotein cholesterol levels, whereas TOR can increase the high-density lipoprotein cholesterol levels, and there was a significant difference between groups. In the postoperative adjuvant endocrine therapy, TOR and TAM will not negatively impact the hepatic function of breast cancer patients, and TOR is better than TAM in the management of serum lipids; therefore, it may be a better choice for clinical medication.

ASCO 2023: highlights in breast cancer

SummaryThe 2023 annual meeting of the American Society of Clinical Oncology (ASCO) was again held in June 2023 in Chicago. While not immediately practice changing, results from several interesting studies in the field of breast cancer (BC) were reported. In the phase III NATALEE trial, the addition of 3 years of ribociclib to standard adjuvant endocrine therapy resulted in a significant improvement in invasive disease-free survival (iDFS), making this the second positive study of CDK4/6 inhibitors in the adjuvant setting. A subgroup analysis from the MONARCHe trial indicated sustained benefit of adjuvant abemaciclib in the subset of patients with low dose intensity. Long-term outcome of the neoadjuvant phase II PHERgain trial indicated excellent iDFS results in patients receiving neoadjuvant trastuzumab and pertuzumab without chemotherapy based upon PET metabolic response as a dynamic biomarker. In a biomarker analysis from the SOFT trial, more high-risk tumors were observed in the very young patient subset, while the PAM50 risk-of-recurrence score was not predictive for benefit of ovarian function suppression. A large retrospective analysis evaluated the role of adjuvant chemotherapy in small, node-negative triple-negative breast cancer. A clear benefit for chemotherapy was only seen in tumors > 10 mm of size. In metastatic HR-positive breast cancer, the PALMIRA trial with palbociclib beyond progression yielded negative results. An update from the PADA-1 trial again indicates the promising role of repeated liquid biopsies for treatment guidance in metastatic disease. Patritumab deruxtecan, a HER3-directed antibody–drug conjugate yielded promising response rates in HER2-negative metastatic breast cancer patients. In addition, several retrospective analyses focused on the important question of treatment sequencing.

Abstract P3-05-28: Impact of increased adiposity on extended aromatase inhibitor treatment in postmenopausal patients with estrogen receptor positive (ER+) breast cancer: a retrospective analysis of the SOLE trial

Abstract Background: The risk of late distant recurrence (≥ 5 years) in post-menopausal patients with ER+ BC remains significant even after standard adjuvant endocrine therapy (ET). Obesity, which has reached high proportions in Western Countries, is one of the modifiable factors that can contribute to BC recurrences. While body mass index (BMI) is an easily available surrogate measure of adiposity, it might not reflect accurately patient adiposity, especially in post-menopausal patients. We therefore hypothesize that mammary adipocyte measurements might better capture the adiposity of the patient. In this study, we retrospectively evaluated the prognostic role of both BMI and adipocyte measurements in the SOLE trial. Patients & Methods: The SOLE trial (NCT00553410) consisted of 4,884 postmenopausal women with hormone receptor positive, lymph node-positive BC treated with 5 years of letrozole after having completed 4-6 years of adjuvant ET. BMI was available for 3,606 patients with ER+/HER2- BC and categorized according to the WHO classification (underweight: < 18.5, normal weight 18.5 – 24.9, overweight 25 – 29.9, obesity ≥ 30 kg/m2). Considering the small sample size, patients with underweight (n=35) were grouped together with patients with normal weight for the subsequent analyses. We evaluated the association between clinico-pathological characteristics and BMI using Fisher exact test and Kruskal-Wallis test. Given the previously reported association of BMI with distant recurrences (PMID: 21115856), we considered distant-relapse free interval (DRFI) as the main study endpoint. Cox regression analyses were adjusted for histology, chemotherapy (yes/no), type of local therapy, in addition to previously reported clinico-pathological variables (PMID: 29158011). Then, we conducted a stratified case-cohort study consisting of 311 patients (97 with distant relapse-cases) with successful digital assessment of adipocytes on normal mammary adipose tissue sample collected at surgery, as previously described (PMID: 33120083). Stratification factors were treatment arm and type of prior ET. Weighted Cox regression models (PMID: 17554753, 18712477) were used to evaluate prognostic association with adipocyte size (area in µm²) categorized in quartile of the 75th percentile (Q4 vs Q1-3), as done previously (PMID: 33753731). Results: 1392 (39%) patients were normal weight, 1315 (36%) were overweight and 899 (25%) were obese. Older age at diagnosis, lymph node involvement (≥4), large tumor size and menopausal status were associated with overweight and obesity. After a median follow-up of 84 months, no associations were found between DRFI and BMI in the univariable and multivariable analysis (adjusted HR overweight vs normal=0.99, 95%CI: 0.76 – 1.29, p=0.977 and HR obese vs normal=1.11, 95%CI: 0.84 - 1.47, p=0.425). In the case-cohort study, patients with larger adipocytes had an increased hazard of distant recurrence in the univariable and multivariable analysis (see table 1). Conclusion: In this study, we did not detect any association between BMI and survival outcomes. We however found that larger mammary adipocytes were independently associated with an increased hazard of distant recurrence. These results suggest that mammary adipocytes, which can be easily evaluated on H&E slides using digital pathology, should be considered as a novel marker to evaluate the risk of late recurrence in patients with breast cancer. Citation Format: Edoardo Isnaldi, François Richard, Giuseppe Marano, Patrizia Boracchi, Marion Maetens, Giuseppe Floris, Guy Jerusalem, Andrea Gombos, Alastair M. Thompson, Erika Hitre, Stefan Aebi, Marco Colleoni, Patrizia Dell’Orto, Roswitha Kammler, Patrick Neven, Giuseppe Viale, Meredith Regan, Elia Biganzoli, Christine Desmedt. Impact of increased adiposity on extended aromatase inhibitor treatment in postmenopausal patients with estrogen receptor positive (ER+) breast cancer: a retrospective analysis of the SOLE 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 P3-05-28.

Abstract GS1-07: Results from a phase III randomized, placebo-controlled clinical trial evaluating adjuvant endocrine therapy +/- 1 year of everolimus in patients with high-risk hormone receptor-positive, HER2-negative breast cancer: SWOG S1207

Abstract BACKGROUND: Abnormalities of the PI3kinase/AKT/mTOR signaling network are common in breast cancer (BC) and are associated with endocrine resistance. Everolimus, an mTOR-inhibitor increased PFS when combined with endocrine therapy (ET) in the metastatic setting and is thought to revert endocrine resistance. S1207 is a phase III randomized, placebo-controlled trial evaluating the role of everolimus in combination with ET in the adjuvant setting among patients with high-risk hormone receptor-positive, HER2-negative BC (NCT01674140). METHODS: Eligible patients were >18 years of age with histologically confirmed invasive hormone receptor-positive and HER2-negative high-risk BC. Four risk groups were defined as: 1) > 2cm node-negative disease (or pN1mi), and either an Oncotype DX® Recurrence Score (RS) > 25 or MammaPrint® high-risk category (MP high); 2) 1-3 positive nodes and either RS >25, MP high or a pathological grade 3 tumor; 3) >4 positive lymph nodes. Patients treated with neoadjuvant chemotherapy were eligible if: 4) after surgery had >1 lymph node involvement. Patients were randomized 1:1 to physician’s choice adjuvant ET in combination with one year of everolimus (10 mg PO daily) or ET plus placebo stratified by risk group. The primary endpoint was invasive disease-free survival (IDFS) evaluated by a stratified log-rank test. Secondary endpoints included overall survival (OS) and safety. The hazard ratio (HR) for treatment efficacy was estimated using Cox regression with stratification by risk groups. Subset analyses included preplanned evaluation within risk group and exploratory analyses of menopausal status and age. RESULTS: 1,939 patients were randomized between September 2013 and May 2019, of them 1,792 were eligible and included in the analysis (896 per arm). Primary reason for ineligibility was timing after chemotherapy/radiation or not high risk. Median age was 54 years (22-85) and 32% were premenopausal. With a median follow-up of 50.5 months, there were 389 IDFS events as of May 2022 (data cutoff). 5-year IDFS was 74.8% among patients treated with everolimus and 73.9% among patients treated with placebo, HR=0.93 (95% CI 0.76-1.14). However, the proportional hazards assumption was violated (p=0.02) suggesting differential treatment effect over time. The HR during the one year of treatment was 0.72 (95% CI 0.47-1.10) while after one year it was 1.00 (95% CI 0.80-1.26). The 5-year OS was 87.6% in the everolimus arm and 85.5% in the placebo arm, HR=0.98 (95% CI 0.75-1.28). Analysis by risk group did not show higher everolimus benefit as risk increased. No difference in IDFS or OS was seen among postmenopausal patients (IDFS HR=1.08 [95% CI 0.85-1.36], OS HR=1.19 [95% CI 0.87-1.61]). Among premenopausal patients, everolimus was associated with improved IDFS (HR=0.63 [95% CI 0.43-0.93]) and OS (HR=0.48 [95% CI 0.26-0.88]). Treatment completion of randomized therapy was lower in the everolimus arm compared to placebo (47.9% v 72.7%). Grade 3 and 4 toxicities were noted in 6.5% and 0.5% of patients in the placebo arm and in 31.2% and 3.7% in the everolimus arm respectively. CONCLUSIONS: Addition of one year of adjuvant everolimus to standard adjuvant ET did not improve IDFS or OS and was associated with low completion rate and increased AEs. Among premenopausal patients there was a benefit in IDFS and OS that is hypothesis generating. Future translational studies will evaluate potential predictors of everolimus benefit and drug toxicity. Citation Format: Marianna Chavez, Jieling Miao, Lajos Pusztai, Matthew P. Goetz, Priya Rastogi, Patricia A. Ganz, Eleftherios (Terry) Mamounas, Soonmyung Paik, Hanna Bandos, Wajeeha Razaq, Anne O’Dea, Virginia Kaklamani, Andrea L.M. Silber, Lisa E. Flaum, Eleni Andreopolu, Joseph Baar, Albert G. Wendt, Jennifer F. Carney, Priyanka Sharma, Julie R. Gralow, Danika L. Lew, William E. Barlow, Gabriel N. Hortobagyi. Results from a phase III randomized, placebo-controlled clinical trial evaluating adjuvant endocrine therapy +/- 1 year of everolimus in patients with high-risk hormone receptor-positive, HER2-negative breast cancer: SWOG S1207 [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 GS1-07.

Abstract OT1-01-02: EMBER-4: A phase 3 adjuvant trial of imlunestrant vs standard endocrine therapy (ET) in patients with ER+, HER2- early breast cancer (EBC) with an increased risk of recurrence who have previously received 2 to 5 years of adjuvant ET

Abstract Background: Adjuvant ET has been the standard of care for patients with estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-) EBC. A significant proportion of patients with increased risk still experience disease relapse despite available ET and more optimum ET is needed to prevent patients developing incurable metastatic cancer. Distant recurrence risk ranges from 20% to 40% after 5 years of adjuvant ET, depending on clinicopathological (clin-path) features at diagnosis. Consequently, there is a need to further optimize adjuvant treatment, particularly in those patients who are at increased risk of recurrence. Imlunestrant is an orally bioavailable selective estrogen receptor degrader (SERD) with pure antagonistic properties and the potential to overcome ET resistance. In early phase trials, imlunestrant monotherapy showed favorable safety with pharmacokinetic (PK) exposures exceeding fulvestrant and preliminary efficacy in ER+, HER2- advanced breast cancer patients (EMBER, Jhaveri 2022) along with robust biological/pharmacodynamic activity and tolerability in EBC (EMBER-2, Neven). Trial Design: EMBER-4 is a randomized, open-label, global phase 3 study comparing imlunestrant versus physicians’ choice of ET, in patients who are at an increased risk of recurrence based on clin-path features and who have received 2 to 5 years of standard adjuvant ET. Approximately 6,000 patients will be randomized 1:1 to receive imlunestrant (400 mg daily) for 5 years or physicians’ choice of adjuvant ET (tamoxifen or an aromatase inhibitor, AI, dosed per label). Study treatment duration is 5 years. Males and pre-/peri-menopausal women will receive concomitant treatment with a GnRH agonist if receiving imlunestrant or an AI. Stratification factors include time from initial adjuvant ET, use of prior adjuvant cyclin dependent kinase 4/6 inhibitors, nodal status, menopausal status, and geographic region. Eligibility criteria: Eligible patients are adult males and females (pre-, peri- or postmenopausal) with ER+, HER2- EBC who have completed definitive locoregional therapy and have received 2 to 5 years of prior adjuvant ET without disease recurrence, but who are at increased risk of recurrence based on clin-path features at diagnosis. Prior (neo) adjuvant chemotherapy and/or targeted therapy with a CDK4/6- or PARP- inhibitor is permitted. Study endpoints: The primary endpoint is invasive disease-free survival (IDFS), excluding second non-breast primary invasive cancers. Key secondary endpoints include distant relapse-free survival, overall survival, IDFS including second non-breast primary invasive cancers, safety, PK and patient reported outcomes. Recruitment for EMBER-4 begins globally in Q4 2022. Citation Format: Komal Jhaveri, Joyce O’Shaughnessy, Fabrice Andre, Matthew P. Goetz, Nadia Harbeck, Miguel Martín, Francois-Clement Bidard, Zachary M. Thomas, Suzanne Young, Roohi Ismail-Khan, Lillian M. Smyth, Michael Gnant. EMBER-4: A phase 3 adjuvant trial of imlunestrant vs standard endocrine therapy (ET) in patients with ER+, HER2- early breast cancer (EBC) with an increased risk of recurrence who have previously received 2 to 5 years of adjuvant ET [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 OT1-01-02.

Cost-Effectiveness of Abemaciclib in Early Breast Cancer Patients: One Size Fits All or Tailoring to Patients' Needs?

The addition of two years of abemaciclib treatment to standard adjuvant endocrine therapy in all patients with high risk ER+, HER2- early breast cancer (EBC) has been approved by the US Food and Drug Administration (FDA). Pre-selection of patients with an immediate risk of recurrence within the group of clinically high risk patients using detection of minimal residual disease (MRD) using patient-informed circulating tumor DNA assays during follow-up could enhance efficacy. Here, we investigate the cost-effectiveness of the addition of two years abemaciclib in all high risk HR+, HER2- patients and in MRD-guided high risk patients only. Two semi-Markov models were developed to evaluate the cost-effectiveness of adding two years of abemaciclib compared to "standard treatment": 1) "abemaciclib all" and 2) "MRD-guided abemaciclib" using MRD-guidance. Data of the MonarchE trial were used to model the invasive disease-free survival (iDFS). Since iDFS and overall survival (OS) data of abemaciclib were currently limited, abemaciclib effects were extrapolated using a favorable, intermediate and unfavorable effect scenario. The addition of abemaciclib in all high-risk EBC patients prolonged iDFS slightly (0.04 additional quality adjusted life years (QALYs)) and led to higher costs compared to standard ET, leading to a high incremental cost effectiveness ratio (ICER) of €1,551,876/QALY. Neither the favorable effect scenario (additional 1.09 QALYs) was cost-effective (ICER €62,935/QALY), using a willingness-to-pay threshold of €50,000/QALY. The "MRD-guided abemaciclib" strategy resulted in lower costs and an increase in QALYs (1.27) compared to "standard treatment" in the unfavorable effect scenario. The addition of abemaciclib to adjuvant endocrine therapy in all high-risk ER+, HER2- EBC patients is not cost-effective. However, using MRD detection to justify the addition of abemaciclib treatment dominates standard treatment in this cost-effectiveness analysis. Further evaluation of MRD detection in EBC by means of prospective clinical trials assessing clinical utility is recommended and promising in terms of cost-effectiveness.

185 (PB-098) Poster - Cost-effectiveness of abemaciclib in early breast cancer patients: one size fits all or tailoring to patients’ needs

Background: The addition of two years of abemaciclib treatment to standard adjuvant endocrine therapy in all patients with high risk ER+, HER2- early-breast cancer (EBC) has been approved by the European Medicines Agency (EMA). Implementation of this treatment in this setting creates additional burden on patients and will increase health care costs. Pre-selection of high-risk patients using detection of minimal residual disease (MRD) by determination of circulating tumor DNA (ctDNA) in plasma during follow-up is highly promising and could select the patients who will benefit from abemaciclib treatment.

Adjuvant dynamic marker-adjusted personalized therapy comparing endocrine therapy plus ribociclib versus chemotherapy in intermediate-risk HR+/HER2- early breast cancer: ADAPTcycle.

TPS609 Background: The WSG ADAPT trial program focusses on individualization of (neo)-adjuvant decision-making in EBC in a subtype-specific manner. Clinical feasibility of the WSG ADAPT trial goals - early response assessment and subtype-specific therapy tailoring to those patients (pts) who are most likely to benefit - has recently been confirmed by the 5-years survival data of the ADAPT HR+/HER2- clinical trial. Methods: WSG-ADAPTcycle is a prospective, multi-center, interventional, two-arm, (neo)adjuvant, non-blinded, randomized, controlled phase III trial (NCT04055493) investigating whether treatment with the CDK4/6 inhibitor ribociclib (600mg/day) together with ET is superior to standard-chemotherapy (CT) in intermediate-risk HR+/HER2- EBC. Definition of intermediate-risk is either based on Oncotype DX and endocrine responder status (measured by Ki67-response after 2-4 weeks of induction endocrine therapy (ET)) or on low-intermediate baseline Ki67 and high estrogen receptor (ER)/progesterone receptor (PR)-expression (Dowsett et al. NPJ Breast Cancer 2020). Co-primary endpoints are DFS and dDFS. It is planned to screen 5600 pts and to randomize 1670 pts (1002 to ribociclib + ET; 668 to standard CT followed by ET). Study start was in July 2019 (88 sites, enrollment period 42 months) and until date of submission, 3079 pts have been screened and 811 randomized (490 ribociclib / 321 CT). Pre-/postmenopausal pts with histologically confirmed invasive HR+/HER2- EBC with high clinical risk (cT2-4 or Ki-67 20% or G3 or cN+) are eligible if they fulfil the ADAPT intermediate-risk criteria: Recurrence Score (RS) ≤25 plus several risk factors and poor ET responder, RS >25 and ET-responder in p/cN0-1 pts, or RS ≤25 with c/pN2-3 in ET-responder. Direct randomization of premenopausal patients (irrespective of ET-response) with c/pN0 and RS 16-25 or c/pN1 with RS 0-25 is allowed according to investigator´s decision; however, based on the ADAPT results, ET+ovarian function suppression alone is strongly recommended in ET-responders. Treatment duration is 2 years for the ribociclib + aromatase inhibitor (AI) (premenopausal: AI + GnRH)-arm and 16-24 weeks for the CT-arm; neoadjuvant or adjuvant treatment is allowed. The minimum 5-year follow-up phase includes standard adjuvant ET. ePROs are collected using CANKADO; ECG monitoring is performed using a novel eHealth method. Translational analyses: Tumor tissue will be collected prior to ET, after at least 3 weeks of ET, if residual tumor is diagnosed (neoadjuvant treatment), and at recurrence, to identify potential resistance markers. Exploratory tissue biomarker research will be conducted to assess alterations in molecular markers. In addition, ctDNA/ctRNA from optional blood samples will be assessed for mutations and gene expression relevant for HR+/HER2- EBC. Clinical trial information: NCT04055493.

Abstract OT1-10-02: I-SPY2 endocrine optimization protocol (EOP): A pilot neoadjuvant endocrine therapy study with amcenestrant as monotherapy or in combination with abemacicilib or letrozole in molecularly selected HR+/HER2- clinical stage 2/3 breast cancer

Abstract Background: There is no clinical equipoise on the best upfront management of patients with early-stage hormone receptor-positive (HR+)/HER2-negative (HER2-) breast cancer (BC) that is high-risk by clinicopathologic criteria, and low-risk based on molecular profiling. These patients are unlikely to respond to chemotherapy. However, these patients still have risk, often risk of late recurrence, despite standard adjuvant endocrine therapy. Novel endocrine-based strategies that are more effective and tolerable than current standard therapies are needed for this population. Next-generation orally-bioavailable selective estrogen receptor degraders (oSERDs) with improved pharmacokinetic (PK) properties are promising potential therapies for HR+ BC. The oSERD amcenestrant has demonstrated a favorable safety profile and encouraging efficacy in a phase I/II dose escalation and expansion trial for heavily pre-treated patients with HR+ metastatic BC and is an attractive agent for assessment in the neoadjuvant BC setting. The neoadjuvant setting offers a unique opportunity to study novel agents and to assess early biological endpoints. However, one of the challenges in studying endocrine-based strategies in the neoadjuvant setting is the lack of a robust surrogate endpoint to reliably predict response and benefit. The I-SPY2 Endocrine Optimization Protocol (EOP) is a pilot sub-study within the main I-SPY2 TRIAL that will test amcenestrant alone or in combination with abemaciclib or letrozole. EOP will test the feasibility of using the I-SPY2 platform to test novel endocrine-based strategies in the neoadjuvant setting in patients with clinical high-risk, molecular low-risk, HR+/HER2- tumors, and will generate a rich database of imaging, molecular, and pathologic correlative endpoints that may potentially inform the improved assessment of response to neoadjuvant endocrine therapy. Trial Design/Eligibility/Accrual: The I-SPY2 EOP is a prospective, randomized, open-label trial specifically for patients with HR+/HER2-negative MammaPrint (MP) low-risk tumors that are at least 2.5 cm in size. Eligible patients are identified during the screening process for the parent I-SPY2 trial. The planned total accrual for the EOP is 120 patients. Patients are randomized 1:1:1 to one of 3 oral treatment arms: 1) amcenestrant 200 mg daily; 2) amcenestrant 200 mg daily + abemaciclib 150 mg bid; 3) amcenestrant 200 mg daily + letrozole 2.5 mg daily. Patients are treated for 6 months prior to surgery. Premenopausal women must receive concomitant monthly ovarian suppression. Serial breast MRIs, breast biopsies, blood, and patient reported outcomes (PROs) are being collected, and patients will be followed for 10 years for recurrence and survival. Serial dedicated breast PET (dbPET) scans and PKs will be assessed in a subset of patients. Objectives/Statistics: The primary objective of the EOP is to investigate the feasibility of enrolling and treating molecularly-selected patients with early stage HR+/HER2- MP low-risk BC in a randomized neoadjuvant trial using an oral-SERD backbone. Treatment will be determined to be feasible if ≥75% of enrolled patients complete ≥75% of assigned study therapy. Secondary objectives include the safety, tolerability, PROs, and PKs related to amcenestrant +/- abemacilcib and letrozole, as well as the assessment of imaging, pathologic, and molecular correlative endpoints as potential biomarkers of response to neoadjuvant endocrine therapy. Status: This study opened in May 2021. Accrual is ongoing. Citation Format: A. Jo Chien, Kevin M Kalinsky, Julissa Molina-Vega, Rita Mukhtar, Karthik Giridhar, Olufunmilayo I Olopade, Amrita Basu, Smita M Asare, Paul Henderson, Gillian Hirst, Ruixiao Lu, Ella Jones, Nola Hylton, Lamorna Brown-Swigart, Laura J van 't Veer, Douglas Yee, Ingrid Mayer, Laura J Esserman. I-SPY2 endocrine optimization protocol (EOP): A pilot neoadjuvant endocrine therapy study with amcenestrant as monotherapy or in combination with abemacicilib or letrozole in molecularly selected HR+/HER2- clinical stage 2/3 breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT1-10-02.

Safety of adjuvant CDK4/6 inhibitors during the COVID-19 pandemic.

Safety of adjuvant CDK4/6 inhibitors during the COVID-19 pandemic.

Role of abemaciclib in primary breast cancer: a narrative review of MonarchE

Role of abemaciclib in primary breast cancer: a narrative review of MonarchE

EMonarcHER: A phase 3 study of abemaciclib plus standard adjuvant endocrine therapy in patients with HR+, HER2+, node-positive, high-risk early breast cancer.

TPS596 Background: Hormone receptor positive (HR+), human epidermal growth factor receptor 2-positive (HER2+) breast cancer (BC) with high-risk characteristics has a high risk of disease recurrence. Novel therapeutic options for this population are urgently needed. Abemaciclib is an oral, selective, and potent CDK4 & 6 inhibitor administered on a continuous schedule which is approved for HR+, HER2- advanced BC (ABC) as monotherapy and in combination with endocrine therapy (ET). Abemaciclib combined with ET demonstrated a statistically significant improvement in invasive disease-free survival (IDFS) in participants (pt) with HR+, HER2-, node-positive, high risk early breast cancer (EBC) and also clinical activity in HR+, HER2+ ABC. The eMonarcHER trial investigates whether abemaciclib plus ET will improve IDFS in pts with HR+, HER2+, node-positive, high risk EBC. Methods: eMonarcHER is a phase 3 global, randomized, double-blinded, placebo (PB)-controlled trial in participants with HR+, HER2+, node-positive, high risk EBC who have completed adjuvant HER2-targeted therapy (tx). Eligible participants are randomized 1:1 to receive either abemaciclib 150 mg twice daily or PB, plus standard ET. Study intervention period will be ≤26 cycles (approximately 2 years) followed by ≤8 years of ET as medically indicated. Participants must have undergone definitive surgery of the primary breast tumor and have high-risk disease. High-risk disease is defined as (i) detection of residual axillary nodal disease at the time of definitive surgery in participants with prior neoadjuvant (neoadj) tx; or (ii) in patients not receiving neoadj tx, must have either ≥4 pathologically positive axillary lymph nodes (pALNs), or 1-3 pathological pALNs and either: histologic Grade 2-3 and/or primary invasive tumor size ≥5 cm. Participants must have received either adjuvant pertuzumab plus trastuzumab with chemotherapy or adjuvant T-DM1. Stratification factors include treatment with neoadj tx, menopausal status, and region. The study is powered at approximately 80% to detect the superiority of abemaciclib plus ET over PB plus ET in terms of IDFS (as defined by the STEEP system) at a 1-sided α =.025 using a log-rank test. Assuming a hazard ratio of 0.73, this requires approximately 324 events at final IDFS analysis. Key secondary objectives include overall survival, distant relapse free survival, safety, pharmacokinetics, and patient-reported outcomes. The study is planned to start in March 2021. Approximately 525 centers in 23 countries plan to enroll ̃2450 participants. Clinical trial information: NCT04752332.

ADAPTlate: A randomized, controlled, open-label, phase III trial on adjuvant dynamic marker—Adjusted personalized therapy comparing abemaciclib combined with standard adjuvant endocrine therapy versus standard adjuvant endocrine therapy in (clinical or genomic) high-risk, HR+/HER2- early breast cancer.

TPS598 Background: The WSG ADAPT trial program addresses the individualization of (neo)adj. decision-making in EBC. The ADAPT umbrella trial established early predictive molecular surrogate markers for response after a 3-wk endocrine treatment (ET) to omit chemotherapy (CT) in a cohort of early high-risk HR+/HER2- pts. ADAPTlate seeks to improve adj. therapy for pts. at high risk for late disease recurrence, who completed definite locoregional therapy (with / without (neo-)adj. CT) and are under adj. ET. This high-risk population does not derive optimal benefit from standard ET, develops secondary ET resistance, and late recurrences. Methods: Prospective, multi-center, interventional, two-arm, open, randomized, controlled adj. phase III trial (NCT04565054) to investigate additional benefit from 2 years of the CDK4/6-inhibitor abemaciclib combined with ET compared to ET alone in pts. with high-risk HR+/HER2- EBC. Abemaciclib demonstrated to improve outcome in metastatic BC and even in EBC when given as part of primary therapy. Primary objective is to demonstrate superiority of iDFS of abemaciclib + ET vs. standard ET. Secondary objectives include OS, dDFS, occurrence of CNS metastases, QoL, and translational research. Recruitment started in 9/2020 to screen 1250 pts. and to randomize 903 pts. in a ratio 3:2. Until date of submission, 33 pts. were screened and 22 randomized. Pre-/postmenopausal pts. with histologically confirmed invasive HR+/HER2- EBC, 2-6 y after primary diagnosis, with either known high clinical risk (c/pN 2-3 OR high CTS score in pN 0-1 OR non-pCR after neoadj. CT in cN 1 or G3 tumors OR G3 and Ki-67 ≥ 40% in pN 0-1) or known high genomic risk (RS >25 in c/pN 0, RS >18 in c/pN 1 OR high risk Prosigna, EPclin or Mammaprint in pN 0-1) or intermediate clinical, but unknown genomic risk (luminal B-like (G3 or Ki-67 ≥20%) in c/pN 0-1 AND either RS >25 in c/pN 0 or RS >18 in c/p N1 in screening) will be eligible. Treatment duration is 2 years for the abemaciclib + ET (premenopausal: AI + GnRH) arm, followed by at least 3-6 years ET alone. Pts. in control arm will receive 5-8-years ET at investigator´s choice. ePROs are collected using CANKADO. Translational analyses: Exploratory tissue biomarker research to assess alterations in molecular markers. Liquid biopsies (CTC/ctDNA/ctRNA) will be assessed for mutations and gene expression relevant for HR+/HER2- EBC using an appropriate technology at time of testing. Conclusions: ADAPTlate seeks to evaluate whether Abemaciclib + ET is superior to ET alone in pts. with clinical or genomic high-risk EBC even 2-6 years after initial diagnosis. Translational research aims at assessing potential mechanisms of resistance to endocrine and/or CDK4/6 targeted therapy. Clinical trial information: NCT04565054.

Efficacy and safety analysis of Chinese patients in monarchE: Abemaciclib combined with adjuvant endocrine therapy for high risk HR+, HER2- early breast cancer.

522 Background: In monarchE, abemaciclib (oral CDK4&6 inhibitor) plus endocrine therapy (ET) as adjuvant treatment for HR+, HER2- high risk early breast cancer (EBC), demonstrated a statistically significant improvement in invasive disease-free survival (IDFS) compared to ET alone. Here we present the efficacy and safety analysis of Chinese patients from monarchE. Methods: The overall study design was reported previously. Eligible patients were randomized to receive abemaciclib (150 mg BID for 2 years) combined with standard adjuvant ET or ET alone. The primary endpoint was IDFS per STEEP criteria. Secondary endpoints included distant relapse-free survival (DRFS), overall survival, and safety. Exploratory subgroup analyses were conducted among Chinese patients enrolled from Mainland China, Hong Kong, and Taiwan in the intent-to-treat (ITT) population. Results: A total of 501 Chinese patients were randomized to receive abemaciclib plus ET (259 patients) or ET alone (242 patients). At the time of data cutoff (July 8, 2020), 356 (71.1%) patients were still in the 2-year treatment period. A total of 26 IDFS events were observed (11 and 15 events in abemaciclib plus ET and ET arm, respectively). Comparing to ET alone, abemaciclib combined with ET reduced the risk of developing invasive disease or death by 34.3% (HR: 0.657, 95% CI: 0.301, 1.435) for Chinese patients, together with a clinically meaningful improvement in the 2-year IDFS rate (95.6% vs 92.1%). The addition of abemaciclib to ET also resulted in an improvement in DRFS (HR: 0.601, 95% CI: 0.245, 1.477) for Chinese patients, with the 2-year DRFS rate at 96.7% (ET alone: 93.4%). In the abemaciclib arm, the most frequent treatment-emergent adverse events (TEAEs) and grade ≥3 TEAEs: diarrhea (90.3% and 5.0%), leukopenia (76.8% and 21.2%), and neutropenia (76.4% and 23.9%), respectively. Conclusions: Abemaciclib combined with adjuvant ET demonstrated clinically meaningful IDFS and DRFS benefits among Chinese patients with HR+, HER2-, high risk EBC, which was consistent with the ITT population as reported previously. The safety profile of abemaciclib in Chinese EBC patients was consistent with global population and also with that observed in Chinese metastatic breast cancer patients. Clinical trial information: NCT03155997.

ESMO 2020: highlights in breast cancer.

Despite the ongoing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, results of several pertinent studies in the field of breast cancer (BC) were presented in a virtual format at the 2020 European Society of Medical Oncology (ESMO) Congress. Early results of the MonarchE trial investigating the addition of the cyclin-dependent kinase (CDK) 4/6 inhibitor abemaciclib to standard adjuvant endocrine therapy indicated a lower recurrence rate in the combination group in a high-risk population of patients with early stage hormone receptor (HR)-positive/HER2-negative BC. In contrast, the PALLAS study evaluating adjuvant palbociclib could not confirm these results. Subtle differences in the respective trial populations, a higher discontinuation rate in PALLAS, or substance-specific differences may be responsible. In HER2-positive early stage BC, long-term results of the ADAPT-TP trial support the notion that chemotherapy-free treatment may be possible in a subset of patients with favourable response to HER2-directed therapy without compromising long-term outcome. The phase III IMpassion031 trial evaluated the addition of atezolizumab to neoadjuvant anthracycline/taxane-containing chemotherapy in triple-negative BC (TNBC). A significant improvement in terms of pathologic complete remission rate was observed but data concerning long-term outcome must be awaited. Final overall survival (OS) analysis of IMpassion130 confirmed the clinically relevant OS improvement observed with the addition of atezolizumab to first-line nab-paclitaxel in metastatic PD-L1 positive TNBC. In contrast, no benefit was observed with the addition of atezolizumab to solvent-based paclitaxel in a similar population. This contradiction is commonly explained by the need for corticosteroid co-medication with conventional paclitaxel, but the exact reason remains poorly understood. Antibody–drug conjugates (ADCs) have been successfully established in HER2-positive breast cancer; in TNBC, the phase III ASCENT trial compared the ADC sacituzumab govitecan with chemotherapy by physician’s choice in pretreated metastatic patients. A significant improvement in terms of progression-free survival and OS was observed rendering this drug a potential novel standard in this patient population.

Abstract OT-01-02: Adaptlate -a randomized, controlled, open-label, phase-iii trial on adjuvant dynamic marker - adjusted personalized therapy comparing abemaciclib combined with standard adjuvant endocrine therapy versus standard adjuvant endocrine therapy in (clinical or genomic) high risk, hr+/her2- early breast cancer

Abstract Goals: The WSG ADAPT trial program is one of the first new generation trials addressing the issue of individualization of (neo)-adjuvant decision-making in early breast cancer (EBC) in a subtype-specific manner. The first WSG ADAPT umbrella trial (NCT01779206) aimed to establish early predictive molecular surrogate markers for response after a short 3-week induction treatment and to omit chemotherapy in a large cohort of early high risk HR+/HER2- patients. The aim of the ADAPTlate phase-III-trial is to improve adjuvant therapy for patients at high risk for late disease recurrence, who have completed definite locoregional therapy (with or without neoadjuvant or adjuvant chemotherapy) and are under adjuvant endocrine treatment. This high-risk population does not derive optimal benefit from standard ET, often develops secondary resistance against ET and consequently late recurrences. With ADAPTlate, it is planned to evaluate whether patients with high-risk EBC derive additional benefit from adding abemaciclib to ET even 2-6 year after their initial diagnosis. Abemaciclib has been shown to improve outcome in metastatic breast cancer and recently, even in early breast cancer when given as part of primary therapy. Methods: WSG-ADAPTcycle is a prospective, multi-center, interventional, two-arm, non-blinded, randomized, controlled adjuvant phase III trial (NCT not yet assigned). It investigates whether patients with HR+/HER2- EBC identified as high-risk during screening (based on clinical or genomic risk) derive additional benefit from 2 years of the CDK4/6 inhibitor abemaciclib combined with ET compared to ET alone. Starting Q3 2020 (enrollment 36 months, 50 sites), 1250 patients will be screened and 903 randomized in a ratio 3:2 (602 to abemaciclib + ET; 301 to standard ET). Pre-/postmenopausal patients with histologically confirmed invasive HR+/HER2- EBC and 2-6 years after primary diagnosis, with either known high clinical risk (c/pN 2-3 OR high CTS score in pN 0-1 OR non-pCR after neoadjuvant chemotherapy in cN 1 or G3 tumors OR G3 and Ki-67 ≥ 40% in pN 0-1) or known high genomic risk (Oncotype Dx® / RS >25 in c/pN 0, RS >18 in c/pN 1 OR high risk Prosigna®, EPclin® or Mammaprint® in pN 0-1) or intermediate clinical, but unknown genomic risk (luminal B-like (G3 or Ki-67 ≥20%) in c/pN 0-1 AND Oncotype DX® in screening either RS >25 in c/pN 0 or RS >18 in c/p N1) will be eligible. Treatment duration is 2 years for the interventional abemaciclib + ET (premenopausal: AI+GnRH) arm, followed by at least 3-6 years ET alone. Patients in control arm will receive 5-8-years ET at investigator´s choice. ePROs are collected using CANKADO. Primary objective is to demonstrate superiority of invasive disease-free survival (iDFS) of abemaciclib + ET vs. standard ET. Secondary objectives include overall survival (OS), distant disease-free survival (dDFS), occurrence of CNS metastases, quality of life (EORTC QLQ-C30, QLQ-BR23, EQ-5D-5L) and translational research. Translational analyses: Exploratory tissue biomarker research will be conducted to assess alterations in molecular markers (e.g., ESR1, PIK3CA, CCND1, CDKN2A, RB1). In addition, ctDNA/ctRNA from optional blood samples will be assessed for mutations and gene expression relevant for HR+/HER2- EBC using the most appropriate technology at the time of testing. Conclusions: ADAPTlate seeks to evaluate whether enhancing ET with a CDK 4/6 inhibitor is superior to ET alone in patients with clinical or genomic high risk EBC even 2-6 years after their initial diagnosis. Translational research aims at assessing potential mechanisms of resistance to endocrine and/or CDK4/6 targeted therapy. Citation Format: Oleg Gluz, Tom Degenhardt, Norbert Marschner, Matthias Christgen, Hans Heinrich Kreipe, Ulrike Nitz, Ronald Kates, Timo Schinkoethe, Monika Graeser, Rachel Würstlein, Sherko Kuemmel, Nadia Harbeck, West German Study Group. Adaptlate -a randomized, controlled, open-label, phase-iii trial on adjuvant dynamic marker - adjusted personalized therapy comparing abemaciclib combined with standard adjuvant endocrine therapy versus standard adjuvant endocrine therapy in (clinical or genomic) high risk, hr+/her2- early breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr OT-01-02.