Dueck, A.

Abstract Background: The PALLAS trial (ABCSG-42, AFT-05, BIG-14-03) investigates adjuvant palbociclib plus endocrine therapy (ET) versus ET alone in patients (pts) with HR+/HER2− early breast cancer. While palbociclib improves outcomes in metastatic settings, final analysis from PALLAS did not demonstrate benefit in survival outcomes from the addition of palbociclib to ET. A number of pts discontinued palbociclib before the planned 2 year duration though degree of palbociclib exposure was not associated with clinical outcomes. This analysis explores factors predictive of palbociclib early discontinuation and dose reductions, including baseline characteristics, toxicities, and patient-reported outcomes (PROs). Methods: Using the safety population of 5736 pts (2840 receiving palbociclib + ET), we assessed early palbociclib discontinuation within a competing-risks framework (competing events: progression, death). Cumulative incidence curves (Aalen-Johansen estimates) and cause-specific hazard models were used to explore associations with clinical and demographic factors (age, menopausal status, stage, race, endocrine therapy type), key toxicities (neutropenia, anemia, nausea), and baseline PROs (patient assessed quality of life [QoL], anxiety, fatigue, pain, frailty/ dependency, depression, and low income. financial difficulties). An automated model selection based on the Akaike information criterion (AIC) starting from the cause-specific hazard model incorporating all considered predictors including PROs. Results: Early discontinuation of palbociclib not due to progression or death occurred in 1171 pts (41.3%); an additional 343 pts (12.1%) stopped due to results of a futility analysis. In 108 (3.8%) and 2 (0.1%) pts treatment was discontinued due to progression or death. Median time to early discontinuation was 7.7 months in pts that discontinued treatment (median interquartile range 3.45-13.60). Very early discontinuation (≤3 months) occurred in 261 pts (9.2%). Dose reductions to 100mg and 75mg occurred in 1566 pts (55.2%) and 951 pts (33.6%) of 2840 pts, respectively. In univariable analyses, higher age, lower N-stage, and specific baseline PROs (baseline QoL, fatigue, anxiety, depression, frailty/ dependency and financial difficulties) were linked with increased risk of discontinuation. The best-fitting multivariable model identified age, nodal stage (N-stage), low quality of life (QoL), and low income as key predictors of early treatment discontinuation. Conclusions: In the PALLAS trial, our findings highlight the importance of integrating PROs into risk prediction of early treatment discontinuation. Additionally, when starting pts on oral targeted therapies in the adjuvant setting, symptom control, social work and financial counseling resources may support pts at higher risk of non-adherence. This is in line with findings from the ESMO Breast QoL analysis (Bjelic-Radisic et al.), which emphasized the added value of subjective patient-reported outcomes alongside objective clinical parameters in understanding treatment burden and adherence. Support: AFT, ABCSG, Pfizer, ECOG-ACRIN, NSABP Foundation, GBG, BIG; https://acknowledgments.alliancefound.org; ClinicalTrials.gov Identifier: NCT02513394. Citation Format: M. Vetter, A. Wiencierz, M. Gnant, D. Hlauschek, C. Kurzeder, C. Grasic Kuhar, N. Zdenkowski, E. Shinn, J. Suga, D. Egle, J. Meisel, S. Antolin-Novoa, E. Munzone, T. Haddad, S. Loibl, A. Holynskyj, C. Fesl, A. Dueck, A. DeMichele, E. Mayer, on behalf of the PALLAS groups and investigators (ABCSG, AFT, BIG,PReCOG, GBG, NSABP). Predictors of early discontinuation of adjuvant palbociclib in early HR+/ HER2- breast cancer: final analysis of the PALLAS trial integrating patient-reported outcomes [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 PS3-07-14.

Abstract PURPOSE: CDK4/6 inhibitors (CDK4/6i), used in combination with endocrine therapy (ET), are standard of care for advanced and higher risk early stage hormone receptor-positive (HR+), HER2 negative (HER2-) breast cancer. PALLAS investigated the addition of 2 years (y) of palbociclib to adjuvant ET (ET/P) compared to ET alone in patients (pts) with stage II-III HR+/HER2- breast cancer. We now present overall survival (OS) with 7-y outcomes and impact of post-recurrence therapy. PATIENTS AND METHODS: This global phase III trial randomized pts to ET for at least 5 y with or without 2 y of P. Primary endpoint was iDFS; distant recurrence-free survival (DRFS) and OS were preplanned endpoints. Kaplan Meier estimates and hazard ratios (HR) from Cox and Fine & Gray models were performed. Post-recurrence OS was analyzed as time from first distant recurrence (DR) until death. The post-recurrence OS model adjusted for both clin/path factors (including DR-free y, DR site) and time-dependent post-DR therapy (chemo, CDK4/6i). Results: 5,796 pts enrolled at 406 centers in 21 countries worldwide over 3 y. In the intent-to-treat (ITT) population, with a median follow-up of 82.7 months (mo), 7-y outcomes for iDFS, DRFS and OS are shown in the table. DR occurred in 781 pts (377 ET/P, 404 ET alone) with balanced pt/disease characteristics between arms. ET/P had more visceral (46% vs. 36%) and fewer non-visceral (61% vs. 68%) DR compared to ET alone (p=0.03). Unadjusted post-recurrence OS was significantly worse for ET/P vs. ET (median 22.6 vs. 27.9 mo, HR 1.21 (95% CI 1.01-1.46, p=0.04). However, receipt of any post-recurrence CDK4/6i was significantly higher on ET vs. ET/P arms (41% vs. 66%) and time to post-progression CDK4/6i initiation was significantly shorter for those in the ET vs. ET/P arms (HR 0.50, 95% CI 0.41-0.61, p<0.001) adjusting for region, bone/visceral DR type, DR-free time and age. Conversely, time to post-progression chemotherapy initiation was significantly longer for ET alone vs. ET/P arms (HR 1.31, 95% CI 1.07-1.61, p=0.01). However, after adjustment for clinical factors and post-DR treatment, the OS difference was no longer seen (HR 1.05, 95% CI 0.85-1.28, p=0.65). 3-mo landmark analysis showed similar effect on OS after adjusting for CDK4/6i initiation within 3 mo from DR (unadjusted HR 1.24, p=0.03 vs. adjusted HR 1.15, p=0.22). CONCLUSION: The PALLAS trial revealed significant differences in treatment post-DR that impact OS. Reduced/delayed use of metastatic CDK4/6i after adjuvant P was associated with significantly poorer OS, suggesting that patients who relapse after adjuvant CDK4/6i may still benefit from metastatic CDK4/6i. This has implications for optimal treatment in those who relapse after adjuvant CDK4/6i and warrants further study to determine if this is therapy-specific or an overarching biological effect. SUPPORT: AFT, ABCSG, NRG, PrECOG; Pfizer Citation Format: A. DeMichele, A. Dueck, M. Gnant, D. Hlauschek, M. Martin, A. Wolff, G. Rubovsky, F. Henao, O. Hahn, A. Chan, A. Brusky, P. Morris, H. Burstein, G. Huber, D. Anderson, L. Garcia-Estevez, G. Pfeiler, H. Rugo, N. Zdenkowski, S. Gampenrieder, N. Wolmark, D. Sabanathan, K. Miller, D. Cameron, E. Winer, C. Brunner, E. Gauthier, P. O’Brien, C. Fesl, E. Mayer. Adjuvant Palbociclib for ER+ Breast Cancer in the PALLAS Trial (ABCSG-42/AFT-05/PrE0109/BIG-14-13): Post-Recurrence Treatment and Overall Survival [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 RF7-07.

Abstract Background PALLAS trial compared palbociclib plus endocrine therapy (ET) vs. ET alone in stage II-III HR+/HER2- breast cancer. SETER/PR index quantifies transcriptional activity related to estrogen and progesterone receptors and serves as a measure of endocrine sensitivity. In CALGB 9741, low SETER/PR (< 0.75) - reflecting endocrine resistance - predicted survival benefit from adjuvant anthracycline/taxane-based treatment. In PALLAS low SETER/PR was associated with worse prognosis and early recurrence. Early recurrences driven by endocrine-resistant tumors may obscure the benefit of palbociclib by disproportionately contributing events from a more resistant population. We hypothesized that palbociclib efficacy might vary by endocrine sensitivity and prior chemotherapy regimen, with greatest benefit in patients with intermediate SETER/PR index. Methods Invasive disease-free survival (iDFS) was summarized with Kaplan-Meier plots and the treatment arms were compared with a log-rank test. Cox models estimated the hazard ratio (HR) with 95% confidence interval (95%CI) (significance level used was a two-sided 0.05). SETER/PR index was successfully obtained for 3,090 PALLAS patients (TransPALLAS ITT cohort, Metzger et al. ASCO 2024). SETER/PR index cut points (0.75 and 1.50) were proposed from previous studies comparing different adjuvant chemotherapy regimens. Results Table 1 summarizes the efficacy of adjuvant palbociclib by prior (neo)adjuvant chemotherapy regimen. Palbociclib was associated with longer iDFS in the group who received prior anthracycline-paclitaxel chemotherapy (AC-P), though the chemo regimen x palbociclib interaction term was not significant (Table 1). In the 1,132 patients from the TransPALLAS cohort who received AC-P chemotherapy, the 518 (46%) patients with intermediate SETER/PR (0.75≤ SETER/PR <1.50) had longer iDFS with palbociclib (HR 0.58; 95% CI: 0.40-0.84; p=0.004; 7-yr iDFS 80.2% vs. 68.4%), but this subset did not predict palbociclib benefit relative to all others, i.e., 206 (18%) patients with low SETER/PR (<0.75) and 408 (36%) high SETER/PR (≥1.50); P interaction=0.11. Exploratory analysis of SETER/PR index as a continuous variable in patients who received prior AC-P chemotherapy revealed a non-linear relationship with the hazard ratio favoring palbociclib observed in the subset with SETER/PR values between 1.1 and 1.8, compared to all others (P interaction=0.01). Conclusions In PALLAS, we observed a numerical benefit favoring palbociclib among pts treated with adjuvant AC-P; in this subset a moderate level of endocrine transcriptional activity (SETER/PR index between 1.1 and 1.8) predicted palbociclib benefit. These results are hypothesis-generating. Citation Format: O. Metzger, P. O'Brien, K. Ballman, M. Gnant, M. Watson, E. Chen, K. Tran, D. Hlauschek, M. Martin, J. Balko, Z. Nowecki, O. Hahn, C. Denkert, C. Curtis, F. Liu, A. Dueck, C. Fesl, E. Mayer, A. De Michele, W. Symmans. Exploratory analysis of palbociclib benefit in the PALLAS trial by SETERPR index and prior chemotherapy regimens (ABCSG-42/AFT-05/BIG-14-13) [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 PS3-08-13.

Abstract Purpose: There are limited prospective data on the efficacy, tolerability, and functional impact of treatments for older and frail adults with HER2+ early breast cancer. We report the first-ever, US-based adjuvant trial dedicated to this population. Methods: We conducted a single arm, phase II, multicenter, investigator-initiated study of adjuvant ado-trastuzumab emtansine (T-DM1) in patients aged 60 and older with stage I-III HER2+ breast cancer who either declined standard adjuvant therapy or were deemed by their physician not to be candidates for standard treatment for any reason. Protocol therapy included postoperative administration of T-DM1 (3.6 mg/kg) every 21 days for one year (17 cycles). The primary endpoint was 5-year invasive disease-free survival (iDFS) with a 2-sided 90% confidence interval. Secondary endpoints presented here are toxicity and 3-year iDFS, invasive breast cancer-free survival (iBCFS), and overall survival (OS). All survival analyses were evaluated using Kaplan Meier methods and began at the time of C1D1 of T-DM1. Results: ATOP enrolled 111 evaluable patients during 2015-2020; median follow-up is 4.9 years (IQR 4.2-5.5). The median age was 71 (range 60-88); 50.4% were aged >70 and 11.7% were aged >80. Overall, 69.4% had stage I, 26.1% had stage II, and 4.5% had stage III disease; 70.3% had hormone receptor-positive tumors. The 5-year iDFS = 84.2% (90% CI 77.1-92.0%). The 3-year iDFS = 91.2% (90% CI 85.9%, 96.9%) and iBCFS = 94.1% (90% CI 89.7-98.8%) (see Table for event details); 3-year OS = 96.1% (90% CI 92.4-99.9%). In total, there were 3 distant recurrences and 2 breast cancer-related deaths. Overall, 82% reported grade 2+ toxicity during treatment; the most common grade 2+ events were fatigue (30.6%) and peripheral sensory neuropathy (19.8%). The most frequent grade 3 events were liver function abnormality, anemia, decreased neutrophil count, and neuropathy (<5% for each); one patient (0.9%) had grade 4 thrombocytopenia. Sixty-five (58.6%) completed all 17 cycles of protocol therapy; 27 (24.3%) completed 10-16 cycles, and 19 (17.1%) completed 1-9 cycles. Reasons for early treatment discontinuation in the remaining 41.4% included toxicity (28.8%), patient withdrawal (6.3%), other (3.6%), disease progression (0.9%), death on study (0.9%, deemed unrelated to treatment), and other complicating disease (0.9%). Conclusions: The ATOP trial demonstrated a favorable 5-year iDFS and manageable toxicity among older adults with early stage HER2+ breast cancer. Although iDFS was numerically worse than historical controls (i.e., 5-year iDFS in the ‘ATEMPT’ trial by Tolaney et al. J Clin Oncol, 2024 was 97% [95% 95.2-98.7]), ATOP’s participants had higher-risk cancers, advanced age, and more competing non-breast cancer events. Future endpoints will include in-depth analyses of patient-reported outcomes, biomarkers of aging, and longitudinal functional status. Citation Format: R. A. Freedman, H. Heiling, K. J. Ruddy, L. Rogak, M. Sedrak, A. Dueck, H. Liu, A. Fraettarelli, S. Atanasov, M. DeMeo, P. Lange, A. Perilla Glen, S. Sinclair, D. Dillon, J. Mortimer, M. Fenton, J. Walsh, L. Spring, H. Muss, N. Sinclair, E. Hamilton, C. Dang, S. Giordano, M. Faggen, S. Lo, C. Kuzma, S. Lemke, P. Stella, R. Mowat, M. Wilkinson, J. Rauch, N. Tayob, E. Winer. Adjuvant Ado-Trastuzumab Emtansine (T-DM1) for Older Patients with HER2+ Breast Cancer - Results from the ATOP 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 PS3-11-04.

Abstract Background: Invasive lobular carcinoma (ILC) accounts for up to 15% of breast cancer (BC) cases and has distinct clinical and biological features compared to invasive carcinoma of no special type (IBC-NST). Prior studies, including PENELOPE-B, suggested greater benefit from adjuvant palbociclib (palbo) in ILC. We assessed the prognostic and predictive value of histology in patients (pts) treated with endocrine therapy (ET) ± palbo. Methods: PALLAS is a global, phase III trial in which pts with stage II-III, HR+/HER2− BC were randomized to 2 years (y) of adjuvant palbo + ET or ET alone. Pts with IBC-NST or pure ILC per local pathology assessment were included. Endpoints included invasive disease-free (IDFS; primary), distant recurrence-free (DRFS), locoregional recurrence-free (LRRFS), and overall survival (OS). Prognostic value was assessed using univariable and multivariate Cox models adjusted for age, T and N stage, grade, and progesterone receptor. Predictive value was assessed using histology-by-treatment interactions. Results: Among 5,748 pts in the ITT population, 4,982 (87%) were included (3,838 IBC-NST [67%], 1,144 ILC [20%]); median follow-up 6.9y. Compared with IBC-NST, ILC was associated with older age (median 54 vs 51 y), higher T stage (T3/T4: 41.7% vs 20.4%), fewer grade 3 tumors (12.7% vs 33.5%), higher mastectomy rates (74.5% vs 58.4%), less (neo)adjuvant chemotherapy (72.2% vs 86.2%), and less tamoxifen as initial ET (28.8% vs 34.5%) (all p<0.001). ILC prevalence varied by country: lower in Asia (Japan 10.5%, Korea 0%, Taiwan 2.8%) and higher in Europe (23.1%) and North America (24.0%). When evaluating the predictive value, palbo appeared to confer greater benefit in ILC for all endpoints (HRs ranging from 0.41 to 0.86) and not in IBC-NST (HRs ranging from 0.97 to 1.01), although the histology-by-treatment interaction was significant only for LRRFS (Table). In the overall population, 7-year IDFS was 79.3% for IBC-NST and 75.8% for ILC. While the difference was significant in univariable analysis (HR 1.17, 95% CI 1.01-1.35), it was not in multivariable analysis (HR 1.06, 0.91-1.24). Notably, the proportional hazards assumption was violated, and time-dependent modeling demonstrated that worse outcomes for ILC on IDFS, DRFS, and other endpoints emerged predominantly beyond 3 years. Conclusions: In this large, randomized dataset of pts with early HR+/HER2− breast cancer with long-term follow-up, ILC demonstrated distinct clinicopathologic features and geographic distribution. While ILC was not an independent prognostic factor over the entire follow-up, time-dependent modeling revealed worse long-term outcomes which only emerged after 3 years. Palbo appeared to be associated with more favorable outcomes in ILC than in IBC-NST across endpoints. These findings suggest a potential benefit of palbo in ILC that warrants further investigation in other adjuvant trials evaluating CDK4/6 inhibitors. Citation Format: G. Nader-Marta, C. Desmedt, D. Hlauschek, A. DeMichele, G. Zoppoli, E. Blondeaux, E. de Azambuja, M. Bellet-Ezquerra, O. Metzger-Filho, J. M. Suga, G. Pfeiler, M. P. Goetz, M. Ruiz-Borrego, S. Loibl, J. Meisel, A. Ring, K. Van Baelen, E. P. Mamounas, N. Zdenkowski, E. Agostinetto, M. Lambertini, E. Gauthier, L. Soelkner, A. C. Dueck, M. Gnant, E. L. Mayer. Long-term prognostic and predictive value of lobular histology in the PALLAS trial [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 PS3-11-06.