Gnant, Michael

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 (PALbociclib CoLlaborative Adjuvant Study, NCT02513394) is a randomized phase III trial comparing two years of the CDK4/6 inhibitor palbociclib combined with the physician’s choice of adjuvant endocrine therapy, versus endocrine therapy alone for patients with Stage II-III hormone receptor-positive, HER2-negative (HR+/HER2-) breast cancer. Molecular residual disease (MRD) detection via circulating tumor DNA (ctDNA) testing was a predefined biomarker analysis to identify patients at highest risk of recurrence. Methods: PALLAS participants with available tumor block, at least a baseline (pre-study treatment) plasma sample, and either whole blood or buffy coat were randomly selected from the overall study population. Plasma samples on cycle 1 day 1 (C1D1), cycle 6 day 1 (C6D1), and at the end of treatment (EOT) were collected, processed, and stored. Nucleic acids were extracted from primary tumor tissue or, when primary tissue was insufficient, from post-neoadjuvant tumor tissue, provided the sample had sufficient material and tumor cellularity (>25 mm2 tissue area with ≥20% tumor nuclei). Data from next generation sequencing of tumor tissue and matched normal DNA were used to create a personalized ctDNA SignateraTM assay (Natera, Inc.) for MRD assessment in the peripheral blood. ctDNA was reported as mean tumor molecules/mL (MTM/mL) of plasma. The primary endpoint was distant recurrence-free interval (DRFI) based on ctDNA status. Cox Proportional Hazards models were used to evaluate prognosis and predictive interactions. To minimize bias, the biorepository and laboratory teams were blinded to participant identity. Results: In total, 1280 participants were randomly selected for inclusion in this preplanned ctDNA sub-study. WES and WGS are being conducted on tissue, and Signatera results will be generated. Results for association of MRD status (positive/negative) and MTM/mL with DRFI in the context of 7 year median follow up of this study cohort will be reported. Conclusions: The planned analysis is ongoing and the presented work will provide data from the first randomized phase 3 adjuvant study in HR+/HER2- breast cancer to report MRD status by treatment arm. Citation Format: H. A. Parsons, K. Ballman, E. Heitzer, M. Watson, M. Balic, D. Hlauschek, D. Renner, E. Kalashnikova, G. Steger, J. M. Balko, Y. Novik, M. Martin, A. A. Rodriguez, Z. Dayao, A. Chan, E. Nili Gal-Yam, M. C. Liu, C. Isaacs, M. Los, M. Gil Gil, B. Felder, C. Denkert, P. Fasching, F. Liu, T. O'Donnell, E. L. Mayer, M. Gnant, W. F. Symmans, A. DeMichele. Tumor-informed circulating tumor DNA analysis to assess molecular residual disease for prognosis and prediction of benefit from palbociclib 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 RF3-04.

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 Background: We have identified two potentially predictive signatures of palbociclib resistance: the RBsig, composed of E2F1/E2F2 dependent genes, which is associated with genetic loss of RB1, and the ratio between the gene expression levels of CCNE1 to RB1 (CCNE1/RB1). Both signatures have been previously analyzed in vitro and in neoadjuvant and metastatic studies with palbociclib. The present analysis aims to explore the role of RBsig and CCNE1/RB1 in the phase III adjuvant PALLAS trial, which randomized patients to palbociclib plus endocrine therapy, versus endocrine therapy alone. Materials and methods: Gene expression data from PALLAS were generated using the HTG EdgeSeq Oncology BM Panel. Of the 87 genes composing RBsig, 46 were available within the EdgeSeq dataset and were used for the analyses; CCNE1 and RB1 were both available. RBsig was calculated as the mean of the Z-score scaled gene expression (log) of the 46 genes; CCNE1/RB1 was computed as the log ratio between the mRNA expression of CCNE1 and RB1. The prognostic/predictive effect of the continuous signatures in terms of invasive disease-free survival (IDFS), distant recurrence-free survival (DRFS), and overall survival (OS) was evaluated using Cox proportional hazard models. Results: HTG data were available from 2,587 of 5,748 patients from the entire PALLAS intention-to-treat (ITT) cohort. As RBsig and CCNE1/RB1 levels are affected by pre-surgical treatments, we limited the analyses to 1612 pre-treatment samples (530 core biopsies and 1082 surgical specimens) (analysis population). Compared with the entire PALLAS ITT cohort, the analysis population was significantly enriched for patients with low clinical risk (41.3% vs 59.4%) who did not receive prior chemotherapy (17.5% vs 55.9%). In keeping with the PALLAS ITT cohort, no significant benefit from the addition of palbociclib was observed in the analysis population. Higher baseline RBsig or CCNE/RB1 values were significantly and independently associated with worse IDFS (hazard ratio [HR] 1.63, 95% confidence interval [CI] 1.3-2.0; HR 1.22, 95%CI 1.1-1.3, respectively), DRFS (HR 1.94, 95%CI 1.5-2.5; HR 1.26, 95%CI 1.1-1.4, respectively) and OS (HR 1.79, 95% CI 1.3-2.4; HR 1.26, 95%CI 1.1-1.4, respectively) in the analysis population. No predictive effect of palbociclib benefit was observed for either signature in the analysis population, nor according to clinical risk or chemotherapy receipt. Interestingly, higher RBsig was strongly prognostic in patients who did not receive adjuvant chemotherapy (HR 1.83, 95%CI 1.4-2.3) but not in those who received it (HR 1.01, 95%CI 0.6-1.6) (interaction p=0.02) suggesting a potential predictive role of RBsig for chemotherapy benefit. Conclusions: In the PALLAS trial, higher baseline RBsig or CCNE1/RB1 values are associated with worse prognosis, but are not predictive of benefit from palbociclib in the adjuvant setting. RBsig might be associated with differential benefit from chemotherapy. Further study of these biomarkers may strengthen their role in risk stratification.https://acknowledgments.alliancefound.org Citation Format: L. Malorni, D. Hlauschek, E. Mayer, M. Benelli, L. Biganzoli, I. Migliaccio, A. Kermanidis, G. Pfeiler, E. P. Mamounas, A. M. Brufsky, M. Bellet-Ezquerra, K. Clifton, G. Rubovszky, T. Foukakis, M. Goetz, S. Lee, M. Ruiz-Borrego, W. Symmans, K. V. Ballman, F. Liu, J. Machacek-Link, C. Denkert, A. DeMichele, M. Gnant. Prognostic and predictive role of RBsig and CCNE1/RB1 gene-expression signatures for patients with early breast cancer treated with endocrine therapy with or without palbociclib in the PALLAS trial (ABCSG-42, AFT-05, BIG 14-03) [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 PS2-07-13.

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.

PURPOSE BMI affects breast cancer risk and prognosis. In contrast to cytotoxic chemotherapy, CDK4/6 inhibitors are given at a fixed dose, irrespective of BMI or weight. This preplanned analysis of the global randomized PALLAS trial investigates the impact of BMI on the side-effect profile, treatment adherence, and efficacy of palbociclib. METHODS Patients were categorized at baseline according to WHO BMI categories. Neutropenia rates were assessed with univariable and multivariable logistic regression. Time to early discontinuation of palbociclib was analyzed with Fine and Gray competing risk models. Unstratified Cox models were used to investigate the association between BMI category and time to invasive disease-free survival (iDFS). 95% CIs were derived. RESULTS Of 5,698 patients included in this analysis, 68 (1.2%) were underweight, 2,082 (36.5%) normal weight, 1,818 (31.9%) overweight, and 1,730 (30.4%) obese at baseline. In the palbociclib arm, higher BMI was associated with a significant decrease in neutropenia (unadjusted odds ratio for 1-unit change, 0.93; 95% CI, 0.91 to 0.94; adjusted for age, race ethnicity, region, chemotherapy use, and Eastern Cooperative Oncology Group at baseline, 0.93; 95% CI, 0.92 to 0.95). This translated into a significant decrease in treatment discontinuation rate with higher BMI (adjusted hazard ratio [HR] for 10-unit change, 0.75; 95% CI, 0.67 to 0.83). There was no significant improvement in iDFS with the addition of palbociclib to ET in any weight category (normal weight HR, 0.84; 95% CI, 0.63 to 1.12; overweight HR, 1.10; 95% CI, 0.82 to 1.49; and obese HR, 0.95; 95% CI, 0.69 to 1.30) in this analysis early in follow-up (31 months). CONCLUSION This preplanned analysis of the PALLAS trial demonstrates a significant impact of BMI on side effects, dose reductions, early treatment discontinuation, and relative dose intensity. Additional long-term follow-up will further evaluate whether BMI ultimately affects outcome.

PURPOSE The PALLAS study investigated whether the addition of palbociclib, an oral CDK4/6 inhibitor, to adjuvant endocrine therapy (ET) improves invasive disease-free survival (iDFS) in early hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2–) breast cancer. In this analysis, we evaluated palbociclib exposure and discontinuation in PALLAS. METHODS Patients with stage II-III HR+, HER2– disease were randomly assigned to 2 years of palbociclib with adjuvant ET versus ET alone. The primary objective was to compare iDFS between arms. Continuous monitoring of toxicity, dose modifications, and early discontinuation was performed. Association of baseline covariates with time to palbociclib reduction and discontinuation was analyzed with multivariable competing risk models. Landmark and inverse probability weighted per-protocol analyses were performed to assess the impact of drug persistence and exposure on iDFS. RESULTS Of the 5,743 patient analysis population (2,840 initiating palbociclib), 1,199 (42.2%) stopped palbociclib before 2 years, the majority (772, 27.2%) for adverse effects, most commonly neutropenia and fatigue. Discontinuation of ET did not differ between arms. Discontinuations for non–protocol-defined reasons were greater in the first 3 months of palbociclib, and in the first calendar year of accrual, and declined over time. No significant relationship was seen between longer palbociclib duration or ≥ 70% exposure intensity and improved iDFS. In the weighted per-protocol analysis, no improvement in iDFS was observed in patients receiving palbociclib versus not (hazard ratio 0.89; 95% CI, 0.72 to 1.11). CONCLUSION Despite observed rates of discontinuation in PALLAS, analyses suggest that the lack of significant iDFS difference between arms was not directly related to inadequate palbociclib exposure. However, the discontinuation rate illustrates the challenge of introducing novel adjuvant treatments, and the need for interventions to improve persistence with oral cancer therapies.

PURPOSE Palbociclib is a cyclin-dependent kinase 4 and 6 inhibitor approved for advanced breast cancer. In the adjuvant setting, the potential value of adding palbociclib to endocrine therapy for hormone receptor–positive breast cancer has not been confirmed. PATIENTS AND METHODS In the prospective, randomized, phase III PALLAS trial, patients with hormone receptor–positive, human epidermal growth factor receptor 2–negative early breast cancer were randomly assigned to receive 2 years of palbociclib (125 mg orally once daily, days 1-21 of a 28-day cycle) with adjuvant endocrine therapy or adjuvant endocrine therapy alone (for at least 5 years). The primary end point of the study was invasive disease-free survival (iDFS); secondary end points were invasive breast cancer–free survival, distant recurrence-free survival, locoregional cancer-free survival, and overall survival. RESULTS Among 5,796 patients enrolled at 406 centers in 21 countries worldwide over 3 years, 5,761 were included in the intention-to-treat population. At the final protocol-defined analysis, at a median follow-up of 31 months, iDFS events occurred in 253 of 2,884 (8.8%) patients who received palbociclib plus endocrine therapy and in 263 of 2,877 (9.1%) patients who received endocrine therapy alone, with similar results between the two treatment groups (iDFS at 4 years: 84.2% v 84.5%; hazard ratio, 0.96; CI, 0.81 to 1.14; P = .65). No significant differences were observed for secondary time-to-event end points, and subgroup analyses did not show any differences by subgroup. There were no new safety signals for palbociclib in this trial. CONCLUSION At this final analysis of the PALLAS trial, the addition of adjuvant palbociclib to standard endocrine therapy did not improve outcomes over endocrine therapy alone in patients with early hormone receptor–positive breast cancer.

Abstract Purpose: Controversy exists about CYP2D6 genotype and tamoxifen efficacy. Experimental Design: A matched case–control study was conducted using the Austrian Breast and Colorectal Cancer Study Group Trial 8 (ABCSG8) that randomized postmenopausal women with estrogen receptor (ER)-positive breast cancer to tamoxifen for 5 years (arm A) or tamoxifen for 2 years followed by anastrozole for 3 years (arm B). Cases had disease recurrence, contralateral breast cancer, second non–breast cancer, or died. For each case, controls were identified from the same treatment arm of similar age, surgery/radiation, and tumor–node—metastasis (TNM) stage. Genotyping was conducted for alleles associated with no (PM; *3, *4, *6), reduced (IM; *10, and *41), and extensive (EM: absence of these alleles) CYP2D6 metabolism. Results: The common CYP2D6*4 allele was in Hardy–Weinberg equilibrium. In arm A during the first 5 years of therapy, women with two poor alleles [PM/PM: OR, 2.45; 95% confidence interval (CI), 1.05–5.73, P = 0.04] and women with one poor allele (PM/IM or PM/EM: OR, 1.67; 95% CI, 0.95–2.93; P = 0.07) had a higher likelihood of an event than women with two extensive alleles (EM/EM). In years 3 to 5 when patients remained on tamoxifen (arm A) or switched to anastrozole (arm B), PM/PM tended toward a higher likelihood of a disease event relative to EM/EM (OR, 2.40; 95% CI, 0.86–6.66; P = 0.09) among women on arm A but not among women on arm B (OR, 0.28; 95% CI, 0.03–2.30). Conclusion: In ABCSG8, the negative effects of reduced CYP2D6 metabolism were observed only during the period of tamoxifen administration and not after switching to anastrozole. Clin Cancer Res; 19(2); 500–7. ©2012 AACR.