SERS sensing of the biomolecule of Palbociclib (PCB) adsorbed on Au3 cluster: DFT, reactivity, docking and MD simulations

Canada’s Drug Agency recommends that Itovebi in combination with palbociclib (PAL) and fulvestrant (FUL) be reimbursed by public drug plans for the treatment of adult patients with endocrine-resistant, PIK3CA-mutated, hormone receptor–positive, HER2-negative, locally advanced or metastatic breast cancer, following recurrence on or after completing adjuvant endocrine treatment, only if certain conditions are met. Itovebi in combination with PAL and FUL should only be covered to treat adults with hormone receptor–positive, HER2-negative breast cancer that has spread to nearby tissue or lymph nodes (locally advanced), or to other parts of the body (metastatic); has come back after hormone (endocrine) therapy; and has an abnormal PIK3CA Patients should also have good performance status. Itovebi in combination with PAL and FUL should not be covered if the patient has been previously treated for hormone receptor–positive, HER2-negative metastatic breast cancer with mutations in the PIK3CA gene, or if they have uncontrolled diabetes. Itovebi in combination with PAL and FUL should be prescribed by, then managed under the care of, health care professionals with expertise in managing advanced or metastatic breast cancer. Reimbursement of Itovebi should be discontinued if the cancer becomes worse or there are unacceptable side effects. Price reductions exceeding 90% in the cost of Itovebi as part of the combination regimen with CDK4/6 inhibitor and FUL would be required to achieve an incremental cost-effectiveness ratio below $50,000 per quality-adjusted life-year gained, relative to therapies currently in use.

Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors have emerged as one of the most transformative classes of targeted therapeutics in modern oncology. Despite of their clinical success, especially in hormone receptor-positive breast cancer, the molecular mechanisms driving differential patient response, acquired resistance, and off-target effects remain incompletely understood. In this work, we present a comprehensive and integrative analysis that combines molecular docking, structure-activity relationships, and mechanistic biochemical insights to unravel the key factors governing CDK4/6 inhibitor performance. By evaluating ligand binding dynamics, conformational shifts within the ATP-binding pocket, and the impact of chemical substituents on drug-protein interactions, we reveal a set of structural features that strongly correlate with potency, selectivity, and resistance propensity. Our study further highlights previously overlooked allosteric regions that may serve as next-generation design targets. Together, these findings offer a deeper molecular-level understanding of CDK4/6 inhibition and provide a roadmap for engineering more effective anticancer agents with enhanced specificity and reduced toxicity. This work aims to accelerate rational drug design efforts and support the development of superior therapeutic strategies for CDK4/6-drigen malignancies. This study provides an in-depth computational analysis of three FDA-approved CDK4/6 inhibitors - Abemaciclib (ABB), Palbociclib (PAB), and Ribociclib succinate (RIB) - using DFT, docking, MD simulations, and pharmacokinetic profiling. Structural optimization and vibrational analyses were conducted alongside FMO and MEP mapping to identify reactive sites.

The combination of endocrine therapy and cyclin-dependent kinase 4/6 inhibitor(CDK4/6 inhibitor)is recommended as primary treatment for hormone receptor-positive HER2-negative metastatic or recurrent breast cancer. In this study, we investigated the efficacy and adverse events of CDK4/6 inhibitors as late therapy in patients treated with palbociclib(PLB) and abemaciclib(ABM)2 sequentially. Nine patients were selected with a history of prescriptions for 2 PLB and ABM drugs from December 2017 to November 2024. Efficacy and adverse events were examined retrospectively from the database. As a result, all patients were female, with an average age of 56 years old. There were 8 recurrent cases and 1 case of de novo Stage Ⅳ. Seven cases were changed to ABM after PLB, and 2 cases were changed from ABM to PLB. Median progression- free survival(PFS)as the late therapy for ABM was 29.2 months vs 6.5 months for PLB. One PD and 6 adverse events were the reasons for switching to ABM after taking PLB. Although the number of patients was small, PFS with sequential CDK4/6 inhibitors could be expected to be longer than 6 months, suggesting that the treatment may be useful in extending the time to chemotherapy induction.

In the present work, we have modified glycogen (GLY) with D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) via the esterification reaction to obtain an amphiphilic polymer (TPGS-GLY). The TPGS-GLY conjugation was confirmed by FTIR and MALDI spectrometry. Furthermore, we prepared polymeric nanomicelles (MCs) encapsulated with palbociclib (PLB) using the solvent casting technique and surface decorated with an antiprogrammed cell death-ligand 1 (PD-L1) antibody to target hypoxic breast tumor. Several physicochemical characterizations have been performed. The MCs were found to be stable under storage, salt ion, and serum stability conditions. In vitro drug release profiles at distinct pH levels (5.5 and 7.4) demonstrate endosomal pH-triggered drug release within cells. The cytotoxicity investigation conducted on MCF-7 and MDA-MB-231 cells showed that the targeted MCs had cytotoxicity 30.94 times and 115.9 times higher than pure PLB, respectively. The cellular uptake, apoptosis, and reactive oxygen species studies have been performed for all of the prepared MCs. Ultrasound and photoacoustic imaging (USG/PAI) in DMBA-induced breast cancer rats revealed that the targeted MCs not only eliminated the tumor but also decreased the hypoxic tumor volume and hindered tumor angiogenesis. The clinical dye indocyanine green (ICG) has been utilized to evaluate the targeting efficiency of MCs toward breast tumors using USG/PAI imaging, demonstrating that targeted micelles has enhanced tumor localization. Furthermore, DiD dye has been employed to investigate organ biodistribution through IVIS imaging.

Real-world outcomes with palbociclib, ribociclib, and abemaciclib plus endocrine therapy in HR+/HER2− advanced breast cancer: A multicenter retrospective study

Evaluation of siramesine, β-Lapachone, and palbociclib as novel maintenance therapies after chemotherapy in small cell lung cancer.

Breast cancer (BC) continues to be a significant global health issue, with triple-negative breast cancer being one of the most aggressive forms. Palbociclib (PAL) has shown promising results in BC therapy but suffers from low solubility, poor oral bioavailability, and variable systemic absorption. A polymeric nanocapsule based on PAL-loaded dextran (PAL-DEX-PNC) was developed to enhance its solubility, stability, gastrointestinal tract (GIT) retention and anticancer efficacy. The optimised PAL-DEX-PNC exhibited a particle size, PDI, zeta potential and percentage entrapment efficiency of 217.8 ± 2.15nm, 0.24 ± 0.03, 1.72 ± 1.07mV, and 99.71 ± 3.1%, respectively. PAL-DEX-PNC had sufficient storage stability of 60days at 2-8°C, in simulated GIT conditions and DMEM cell culture media. The PAL release from PAL-DEX-PNC at pH 5.5 and 7.4 was 70.05 ± 3.02% and 62.46 ± 3.43%, respectively, sustained for a period of 48h. The ex vivo permeability studies confirmed an 8.85-fold increase in drug permeability for PAL-DEX-PNC compared to free PAL. The in vitro cytotoxicity assessment on MDA-MB-231 cells revealed that PAL-DEX-PNC has significantly greater cytotoxic potential than free PAL, with a 3.49-fold decreased IC50 value and 2.22-fold enhanced apoptotic index. Furthermore, higher ROS production, depolarisation of MMP and cellular uptake, along with reduced colony formation and wound healing, were evidenced. In addition, a 3.19-fold reduction in 3D mammosphere diameter was seen with PAL-DEX-PNC. The in vivo GIT uptake studies depicted that Nile red-loaded polymeric nanocapsules exhibited 3.68-fold higher fluorescence intensity in the GIT than free Nile red, indicating higher uptake attributed to the mucoadhesive nature of DEX.

Design of peptide functionalized nitrogen doped graphene quantum dots for theranostic application in breast cancer.

Abstract Breast cancer (BC) is the second most predominant malignancy affecting women worldwide, and a variety of treatment options are available to combat this disease. The present study focused on optimizing and evaluating surface‐modified nanoparticles to enhance the therapeutic delivery of palbociclib (PCB) in targeted breast cancer cells. The palbociclib‐loaded nanoparticles were developed via the desolvation method with bovine serum albumin (BSA). The optimized formulation was obtained by applying the Box–Behnken response surface methodology. The surface was modified with folic acid and hyaluronic acid to improve the targeting specificity and cellular uptake in the MCF‐7 breast cancer cell line. The optimized formulations of folic acid‐ and hyaluronic acid‐coated nanoparticles had particle sizes of 107.76 ± 2.05, 171.20 ± 1.53, and 165.72 ± 1.45 nm; zeta potentials of −22.30 ± 1.47, −25.62 ± 1.31, and −28.52 ± 2.32 mV; and entrapment efficiencies of 85.42 ± 1.05%, 85.63 ± 2.81%, and 84.78 ± 2.67%, respectively. Drug release kinetics revealed a diffusion‐controlled mechanism characterized by Fickian diffusion ( n value = 0.4043). The in vitro cell line studies revealed that the nanoparticles coated with folic acid exhibited superior anticancer activity, achieving the lowest IC 50 value, likely due to folate receptor‐mediated targeting. These findings emphasize the potential of folic acid‐coated palbociclib nanoparticles as promising candidates for targeted breast cancer therapy.

Palbociclib (PAL) combined with endocrine therapy (ET) is approved for hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2- ) advanced/metastatic breast cancer (MBC). However, there is limited data on the effectiveness of PAL + ET in patients with MBC and low socioeconomic status. This retrospective study of the Flatiron Health database compared overall survival (OS) and real-world progression-free survival (rwPFS) in patients with MBC living in disadvantaged neighborhoods who received either first-line PAL with an aromatase inhibitor (AI) or an AI alone. Of 723 patients, 394 received PAL + AI and 329 received AI alone. After stabilized inverse probability of treatment weighting, median OS was 57.1 months versus 38.2 months (hazard ratio, 0.70, P = 0.0053) and median rwPFS was 19.1 months versus 14.0 months (hazard ratio, 0.66, P = 0.0007) for PAL + AI versus AI alone, respectively. This real-world data analysis demonstrated that first-line PAL + AI versus AI alone was associated with survival benefit in patients with HR+/HER2- MBC living in disadvantaged neighborhoods. Trial registration number: NCT06495164.

Abstract Introduction: PAL, cyclin-dependent kinases 4 and 6 inhibitor (CDK4/6i), + ET is a standard therapy for the treatment of HR+/HER2- ABC. Efficacy and safety of PAL + ET was shown by two randomized clinical trials, PALOMA-2 and PALOMA-3. Further, recent large real-world studies revealed effectiveness of PAL + aromatase inhibitor (AI) for HR+/HER2- ABC in routine United States clinical practice. To strengthen the real-world evidence (RWE) of PAL + ET for HR+/HER2- ABC treatment under different clinical practice and healthcare situations, we conducted observational study to evaluate the effectiveness of PAL + ET in Japanese real-world setting. Recently, we reported that the median (95% CI) OS were 68.2 months (60.8-not estimated (NE)), among patients who treated with PAL + ET in 1st line (1L) in Japanese routine clinical practice with longer follow-up after interim analysis. Here, we investigate the subgroup of real-world OS of Japanese patients treated with PAL + ET as 1L for HR+/HER2- ABC to understand the impact of OS. Methods: In this multicenter, observational study, patients with HR+/HER2- ABC, who initiated PAL + ET from 15 December 2017 (launch date in Japan) to 31 December 2020 were enrolled. To reduce selection bias, all patients who started PAL during the above period were listed up and eligibility was confirmed. Key eligibility criteria were: 1) Diagnosis of HR+/HER2- ABC; 2) Patients received PAL + ET in 1L or 2L; 3) Patients had at least 6 months of follow up from start of PAL or died within that period. The primary endpoint was real-world progression free survival (rwPFS), and one of the secondary endpoints was OS, defined as the time from start of PAL + ET treatment to death due to any cause. We performed the further analysis, including subgroup analysis, about OS of 1L PAL + ET to investigate what factors could affect its clinical benefits. Results: In this study, 693 patients from 20 study sites in Japan were enrolled. Among them, 426 and 267 received PAL + ET as 1L and 2L, respectively. The median age was 60.0 (range 29-87) and 482 patients (70.0%) were postmenopausal. 54.0% patients had visceral involvement and 43.3% had <12 months of treatment-free interval (TFI; defined as end date of adjuvant therapy to diagnosis date of recurrence). 295 patients received subsequent therapy out of 426 patients after PAL + ET as 1L. 60.7% (179/295) of patients received an endocrine-based regimen as first subsequent treatment; of those 23.1% (68/295) received CDK4/6i + ET, 19.3% (57/295) endocrine monotherapy, and 17.6% (52/295) ET + everolimus. After a median follow-up of 48.1 months, the following subgroup analysis was performed for OS in 1L, showing median OS (95% CI) and, survival rate at 60 months: pre-/post-menopausal status was not reached (NR) (59.4-NE), 61.3%/68.0 months (58.5-NE), 55.6%, TFI<12 months/TFI12>months/De novo metastatic was 56.3 months (43.9-68.2), 46.1%/NR (NE-NE), 72.9%/NR (56.3-NE), 60.0%, visceral/non-visceral metastasis was 65.0 months (56.3-NE), 52.3%/NR (63.2-NE), 61.3%, liver metastasis was 46.4 months (37.2-NE), 42.8%, and bone only disease was NR (57.8-NE), 61.2%. Conclusions: The findings of the study based on Japanese routine clinical practice further confirmed that the clinical benefits of PAL+ET is consistent regardless of patient characteristics in the real-world setting. In all subgroup other than TFI<12 months or liver metastasis, median OS was >5 years with 1L PAL + ET, underlining the use of PAL + ET as 1L standard for ABC in the real-world setting. Citation Format: Michiko Tsuneizumi, Tetsuhiro Yoshinami, Shigenori E. Nagai, Masaya Hattori, Hiroko Masuda, Takuho Okamura, Kenichi Watanabe, Takahiro Nakayama, Daisuke Takabatake, Michiko Harao, Hiroshi Yoshino, Natsuko Mori, Hiroyuki Yasojima, Chiya Oshiro, Madoka Iwase, Miki Yamaguchi, Takafumi Sangai, Shinsuke Sasada, Takanori Ishida, Manabu Futamura, Nobuyoshi Kosaka, Yasuaki Muramatsu, Norikazu Masuda. Real world effectiveness of overall survival (OS) with palbociclib (PAL) plus (+) endocrine therapy (ET) in hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC) patients in Japan [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P4-07-22.

Abstract Background: Endocrine therapy (ET) combined with a CDK4/6 inhibitor is standard of care for hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) locally advanced or metastatic breast cancer (ABC). In Europe, around 40% of BC are diagnosed in women aged ≥70 years, contrasting with their underrepresentation (<5-10%) in clinical trials. PalomAGE is a French prospective, observational, real-life study, assessed the feasibility of palbociclib (PAL) combined with ET in women aged ≥70 years with HR+/HER2- ABC. PalomAGE included a geriatric assessment as recommended in this population when the G8 screening tool identified a probability of frailty. Here, we report the final results in patients with no prior systemic treatment for ABC and no relapse within 1 year after the end of adjuvant ET. Methods: Data collected at baseline and every 3 months included sociodemographic, clinical, biological, disease and treatment response, quality of life (QoL; EORTC QLQ-C30 and ELD14), geriatric (G8 and Geriatric-COre DatasEt [G-CODE]) and safety parameters. Primary endpoint was PAL discontinuation rate (any reason) at 18 months. Secondary endpoints included time-to-treatment failure (TTF), progression-free survival (PFS), geriatric and QoL assessment, and safety. Results: From October 2018 to December 2020, 816 patients were included, among whom 412 patients initiated PAL as first-line. Median age was 78 years (range 70-94) with 44.4% of patients ≥80 years, ECOG was ≥2 in 17.5%, visceral metastasis was present in 41.7%. For patients with geriatric questionnaires completed, baseline scores showed G8 ≤14, ADL ≤5, IADL short form ≤3 and Charlson comorbidity score ≥ 4 in 69.1%, 14.6%, 28.7% and 85.5% of patients, respectively. PAL starting dose was 125 mg, 100 mg, and 75 mg in 80.6%, 14.3%, and 5.1% of patients, respectively, combined with an aromatase inhibitor in 93.2% or fulvestrant in 6.8%. Patients initiating PAL at reduced dose were older (median age 83 years), presented more often an ECOG ≥ 2 (22.5%) and poorer geriatric scores (G8≤14, ADL ≤5, IADL short form ≤3, Charlson comorbidity score ≥4 in 82.1%, 25.4%, 35.8%, 91.9%, respectively). Of all patients, 382 (92.7%) were evaluable for efficacy endpoints. With a median follow-up of 25.2 months (95% CI 21.7-28.4), the 18-month PAL discontinuation rate was 41.4% (95% CI 36.4-46.3) with disease progression (20.7%), toxicity (7.3%), patient’s choice (6.8%), death (4.7%), or other reason (1.8%) as main causes. Median TTF and PFS were 23.0 months (95% CI 19.8–26.0) and 30.4 months (95% CI 25.7-not reached). Higher 18-month PAL discontinuation rate, shorter median TTF and PFS values were observed with PAL initiation at a reduced dose without reaching statistical significance. The univariate analysis showed that baseline factors associated with lower TTF were higher age, poorer ECOG score, greater metastatic sites, G8≤14, IADL short form ≤3, and no person able to provide care and support. The multivariate analysis is in progress. At the end of the study, 93.7% and 38.7% of patients were still alive and under PAL treatment. 80.6% patients presented at least one adverse event (AE) related to treatment, with 63.3% neutropenia all grade (1.0% febrile neutropenia). AE led to PAL dose reduction and permanent discontinuation in 35.2% and 10.7% of patients. Conclusion: PalomAGE confirms the feasibility of ET combined with PAL as first line for HR+/HER2- ABC in unselected women aged ≥70 years with significant prevalence of comorbidities and G8 impaired. Median PFS of 30.4 months is consistent with results obtained with PAL + ET in ET-sensitive HR+/HER2- ABC in other RCT and RW studies (PALOMA-2, PARSIFAL-LONG, PALBOSPAIN), with no new safety signal. Citation Format: Elisabeth Carola, Marina Pulido, Philippe Cailllet, Claire Falandry, Elena Paillaud, Louis Tassy, Michael Bringuier, Godelieve Rochette De Lempdes, Nicolas Jovenin, Axelle Boudrant, Jessica Grosjean, Camille Chakiba-Brugere, Anne-Claire Hardy-Bessard, Hubert Orfeuvre, Eric Legouffe, Fanny Bouteiller, Vincent Launay-Vacher, Maylis Decrop, Etienne Brain. Palbociclib in women aged ≥70 years as first-line treatment for endocrine-sensitive Hormone Receptor-positive/Human Epidermal Growth Factor Receptor 2-negative locally advanced or metastatic breast cancer: final results of PalomAGE [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P2-07-17.

Abstract Background: Palbociclib (PAL), the first CDK4/6i, in combination with endocrine therapy (ET) was approved for HR+/HER2- advanced/metastatic breast cancer (MBC) in 2015. Two additional CDK4/6is, Ribociclib (RIB) and Abemaciclib (ABE), were approved in 2017. CDK4/6i combination therapy has become standard of care for 1st line HR+/HER2- MBC. Randomized clinical trials (RCT) demonstrated that the 3 CDK4/6is plus ET vs ET plus placebo all significantly prolonged patients’ progression free survival (PFS, primary endpoint). However, the 3 CDK4/6is have inconsistent 1st line RCT overall survival findings (OS, secondary endpoint). In the absence of head-to-head RCTs, real-world data (RWD) is an important complementary source of evidence. Several small RWD studies have evaluated the relative effectiveness between CDK4/6is, and their findings are inconsistent. Large RWD studies are needed to understand the effectiveness of the 3 CDK4/6is. This study compared OS of 1st line PAL vs RIB and ABE plus AI for HR+/HER2- MBC in routine US clinical practice. Methods: We conducted a retrospective comparative effectiveness study of CDK4/6is plus AI in HR+/HER2-MBC using the US nationwide Flatiron Health electronic health record (EHR)-derived deidentified Panoramic database, comprised of >650k patients with breast cancer. Patients included had HR+/HER2- MBC, were ≥18 years, started index treatment (PAL+AI, RIB+AI, or ABE+AI) as 1st line therapy within 90 days of MBC diagnosis between February 2015 and September 2023 (index period), and did not participate in clinical trials. Patients were assessed from start of index treatment to March 2024, death, or last medical activity, whichever came first. OS was defined as months from start of index treatment to death. Patients were balanced via exact 1:1 matching on age, gender, race and ethnicity, practice type, disease stage at initial diagnosis, ECOG, time from initial to MBC diagnosis, visceral disease, bone-only disease, and number of metastatic sites. Kaplan-Meier method and Cox proportional hazard regression model were used to analyze OS. Results: Of 9770 patients eligible for the analysis, 7563, 1130, and 1077 patients received PAL+AI, RIB+AI, and ABE+AI, respectively. Median follow-up was 32.9 months for PAL+AI, 16.5 months for RIB+AI, and 21.3 months for ABE+AI treated patients. Compared with RIB and ABE groups, PAL group was 1-2 years older and had a lower proportion of patients with ECOG=0. After 1:1 matching, baseline demographics and clinical characteristics were well balanced between PAL vs RIB pairs (n=942) and PAL vs ABE pairs (n=857). In PAL-RIB pairs, 2- and 3-year OS rates were 81.3% and 67.6% for PAL group vs 79.8% and 69.7% for RIB group. In PAL-ABE pairs, 2- and 3-year OS rates were 76.8% and 63.0% for PAL group vs 75.7% and 67.4% for ABE group. Compared with PAL+AI, RIB+AI was not significantly associated with prolonged OS (unadjusted HR=0.90, 95%CI=0.80-1.02, p=0.097; matched HR=0.98, 95%CI=0.84-1.15, p=0.823). Similarly, ABE+AI vs PAL+AI was not significantly associated with prolonged OS (unadjusted HR=0.95, 95%CI=0.84-1.07, p=0.376; matched HR=0.90, 95%CI=0.77-1.06, p=0.212). Further analyses with additional follow-up, treatment duration, subsequent therapies, and time to chemotherapy will be reported. Conclusions: Our findings suggest that there is no significant OS superiority of first-line RIB+AI and ABE +AI compared to PAL+AI for HR+/HER2- MBC patients in routine clinical practice in the US. Although the sample size precludes a formal non-inferiority analysis and short follow up may limit interpretation, this study represents the largest real-world comparative analysis of OS between the CDK 4/6is in combination with AI conducted to date. Citation Format: Hope S. Rugo, Rachel M. Layman, Filipa Lynce, Xianchen Liu, Benjamin Li, Lynn McRoy, Aaron B. Cohen, Melissa Estevez, Giuseppe Curigliano, Adam Brufsky.Comparative overall survival of CDK4/6is plus an aromatase inhibitor (AI) in HR+/HER2- MBC in the US real-world setting [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr PS2-03.

Abstract Background: A cyclin dependent kinase 4/6 inhibitor (CDK4/6i) in combination with endocrine therapy has become standard of care for HR+/HER2- advanced/metastatic breast cancer (MBC). CDK4/6i dose adjustment is recommended based on individual safety and tolerability during the treatment of MBC. Clinical trial data demonstrated that Palbociclib (PAL) dose adjustment had no significant impact on progression-free survival (PFS). Small real-world studies have not demonstrated consistent outcomes associated with PAL dose adjustment, including real-world PFS (rwPFS) and overall survival (OS). Large real-world studies with longer follow-up are needed to understand patient characteristics and clinical outcomes associated with CDK4/6i dose adjustment. This study examined PAL dose adjustment and outcomes in HR+/HER2- MBC in routine clinical practice. Methods: Using Flatiron Health longitudinal database, we conducted a retrospective analysis of HR+/HER2- MBC patients who started PAL plus an aromatase inhibitor (AI) as first-line therapy between February 2015 and March 2020 (index period). Patients were assessed from start of PAL+AI to September 30, 2020 (data cutoff), death, or last medical activity, whichever came first. Dose adjustment was defined as a change of PAL daily dose compared to initial/previous prescription dose. Treatment duration was defined as months from start of PAL+AI to end of the treatment. OS was defined as months from start of PAL+AI to death. rwPFS was defined as months from start of PAL+AI to death or disease progression, evaluated based on clinical assessment or radiographic scan/tissue biopsy. Kaplan-Meier analysis was used to estimate treatment duration, rwPFS, and OS. Multivariable Cox proportional hazard regression models were performed to adjust for baseline characteristics: age, sex, race/ethnicity, healthcare practice type, initial diagnosis, Eastern Cooperative Oncology Group Performance Status, National Cancer Institute-Comorbidity Index, disease free interval from initial breast cancer to MBC diagnosis, bone only disease, lung/liver involvement, and number of metastatic sites. Results: A total of 1,324 patients received PAL+AI during the index period. Mean age was 67.1 years (SD=9.6), 99.2% were female, and 68.0% were white. Of these patients, 1,110 (83.8%) initiated PAL at 125 mg/day, 144 (10.9%) at 100 mg/day, 48 (3.6%) at 75 mg/day, and 22 (1.7%) did not have information about initial dose. Among 1,302 patients who had initial dose documented, 524 (40.3%) experienced dose adjustment. Comparted with patients without dose adjustment, those with dose adjustment were more likely to be white (71.8% vs 65.8%) and had a higher proportion of lung/liver involvement (35.5% vs 32.4%). Median follow-up was 28.5 and 22.6 months in patients with and without dose adjustment, respectively. Median treatment duration was longer in patients with dose adjustment than in those without dose adjustment (27.4, 95%CI = 24.5–30.6 vs 21.4, 95%CI = 19.7–26.5 months). Patients with and without dose adjustment showed similar median rwPFS (20.5, 95%CI=17.8–25.9 vs 19.6, 95%CI=16.9–21.7 months; unadjusted HR = 0.90, 95%CI = 0.77–1.04, p=0.162; adjusted HR = 0.89, 95%CI = 0.76–1.04, p=0.133). Median OS was significantly prolonged in patients with dose adjustment than in those without dose adjustment (57.8, 95%CI=49.0–NA vs 51.4, 95%CI=45.3-58.7 months; unadjusted HR = 0.72, 95%CI = 0.59–0.88, p=0.001; adjusted HR = 0.73, 95%CI = 0.59–0.89, p=0.002). Conclusions: Similar to other CDK4/6is, PAL dose adjustment is common in the treatment of HR+/HER2- MBC. PAL dose adjustment did not have significant effect on rwPFS but was associated with prolonged treatment duration and OS. Further research is needed to confirm these findings and understand the reasons for PAL dose adjustment in real-world settings. Citation Format: Rachel Layman, Xianchen Liu, Benjamin Li, Lynn McRoy, Connie Chen, Gabrielle B Rocque, Adam Brufsky. Real-world palbociclib dose adjustment and outcomes in HR+/HER2- metastatic breast cancer: Flatiron database analysis [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P4-10-14.

Abstract Background: Resistance to ET is a major contributor to BC mortality. CDK4/6i overcomes ET-R. However, some ER+/HER2- BC are intrinsically resistant to ET/CDK4/6i. Here we report the primary endpoint of complete cell cycle arrest (CCCA) and correlative studies of the NeoPalAna (NCT01723774) ET-R Cohort to examine resistance biomarkers for palbociclib (PAL) + anastrozole (ANA). Methods: NeoPalAna is a multi-cohort single arm phase 2 neoadjuvant endocrine (NET) trial of PAL/ANA in clinical stage II/III ER+/HER2- BC. The ET-R Cohort enrolled patients (pts) with tumor Ki67 >10% after at least 4 weeks of standard (SOC) NET to receive PAL/ANA for 4 28-day cycles before surgery if Ki67 was ≤10% on C1D15 biopsy (Ki67C1D15). Pts switched to chemotherapy or underwent surgery if Ki67C1D15 >10%. The primary endpoint was C1D15 CCCA (Ki67C1D15 ≤2.7%). Simon’s optimal 2-stage design (stage 1 n=12, stage 2 n=25) was used to detect a CCCA rate ≥20% vs ≤5% (power 0.9, alpha 0.1). Correlative endpoints included genomic and proteomic analyses of tumor tissues in relation to response by Ki67C1D15 ≤10% (PAL-Sensitive or PAL-S) or >10% (PAL-Resistant or Pal-R). Tumor biopsies prior to SOC ET (Baseline or BL), before PAL/ANA (C1D1), and at C1D15 were analyzed for whole exome sequencing (WES) for 27 pts at the earliest timepoint (13 BL, 5 at C1D1, and 9 at C1D15), RNAseq for 33 pts at all possible timepoints (BL n=20, C1D1 n=15, C1D15 n=28) and global proteomic analysis on 16 C1D15 frozen cores (11 PAL-S and 5 PAL-R). Differentially expressed genes (DEGs) and Hallmark gene set enrichment analyses (GSEA) were performed controlling false discovery rate (FDR). Results: Between Aug 2016 and Mar 2021, 34 pts were enrolled, with a median age 53 (30.4∼77.6) years and a median 6 weeks of prior NET. This ET-R cohort was enriched for high grade tumors (3% G1, 47% G2, 47% G3) and mutations implicated in ET resistance. The top 6 mutated genes included TP53 (41%), PIK3CA (33%), NCOR1 (22%), NF1 (22%), RUNX1 (19%) and CDH1 (19%), similar between PAL-S vs -R BCs. CCCA rate was 57.6% (19/33; 95% CI: 39.2-74.5%). The trial met its primary endpoint (exact binomial test p<0.0001 against null CCCA of 5%). At BL, PAM50 subtype was determined for 20 pts with RNAseq performed, which revealed 8 LumA (all PAL-S), 8 LumB (5 PAL-S, 3 PAL-R) and 4 non-Lum BCs (3 Basal and 1 HER2 E, all PAL-R). Principal component analysis (PCA) of 630 DEGs (FDR adj. p≤0.5) at BL demonstrated tight clustering of PAL-S BCs, with PAL-R BCs appeared to scatter away in a gradient. Top positively enriched DEGs in PAL-R BCs included CCNE1, IDO1, IRF4, BRCA2, EZH2, and several immune cell markers. Top upregulated signaling pathways in PAL-R BCs included interferon (IFN) γ signaling, E2F targets, allograft rejection, MYC targets, G2M checkpoint, mTORC1 and TNF signaling, inflammatory response, IL6-JAK-STAT, and IFN α signaling. Estrogen response pathways were significantly downregulated in PAL-R BCs. Comparing C1 and BL, ET upregulated multiple pathways including allograft rejection, EMT, IFN γ response, etc. Adding PAL led to significant reductions in G2M checkpoints, E2F and MYC targets, IFN, mTOR pathways by both RNA and proteomic analyses. However, these pathways remain highly upregulated in PAL-R vs PAL-S at C1D15. CIBERSORT analysis which deconvoluted bulk RNAseq to estimate and compare cell type fractions at C1D15 and BL indicated a significant increase in several immune cell types including CD8 T cells, Plasma cells, M1 and M2 macrophages, and monocytes in PAL-S but not PAL-R BCs. Conclusion: Neoadjuvant PAL/ANA led to 58% CCCA at C1D15 in ET-R BC. Specific oncogenic pathways and immune tolerance markers, such as IDO1, were enriched in PAL-R. Our data also suggest immune modulatory effects of CDK4/6i/ET in association with ET/PAL response. Citation Format: Tim Kong, Alex Mabry, Jingqin Luo, Anthony Z. Wang, Jeremy Hoog, Zhanfang Guo, Shana Thomas, Yingduo Song, Feng Gao, Mateusz Opyrchal, Lindsay Peterson, Foluso Ademuyiwa, Julie Margenthaler, Rebecca Aft, Katherine Glover-Collins, Leslie Nehring, Yu Tao, Souzan Sanati, Ian Hagemann, Fouad Boulos, Matthew Holt, Li Ding, Wenge Zhu, Jason Weber, Matthew Goetz, Donald Northfelt, Cynthia X. Ma. Molecular characterization of the NeoPalAna Endocrine Resistant (ET-R) Cohort: implications for CDK4/6 inhibitor (CDK4/6i) and ET resistance mechanisms in primary estrogen receptor positive (ER+) and HER2 negative (HER2-) breast cancer (BC) [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr PS12-03.

Abstract Background: PAL is a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) for the treatment of HR+/HER2- ABC. In phase 3 clinical trials, HRQoL was generally maintained and/or improved in patients (pts) treated with PAL+ET compared with placebo+ET. Previously, we reported that PAL+ET and ET monotherapy did not impact on HRQoL or physical activity (SABCS2023, PO1-05-06). Here, we explored potential risk factors related to HRQoL changes in the pts treated with PAL+ET or ET alone evaluated with a mobile application. Methods: This prospective, observational, multicenter study was conducted in Japanese women with HR+/HER2- ABC initiating PAL+ET (Group 1) or ET alone (Group 2) in 1L/2L setting. HRQoL was assessed using EORTC-QLQ-C30 at baseline and Day 15 of each cycle via a smartphone-based app for 6 cycles (24 weeks). Patient data, including baseline characteristics, treatment, and adverse events, were collected via electronic case report forms. A multivariate mixed effects model was conducted to explore risk factors for HRQoL changes, including treatment group, cycle, baseline HRQoL, line of therapy, education, employment, menopausal status, ECOG-PS, TMN stage, BMI, visceral metastases, and dose reduction as fixed effects. This was exploratory analysis and a trend of GHS change and related risk factors were evaluated. Positive score of estimated mean change represents improvement of global health status (GHS), and negative score represents deterioration of GHS. Results: Ninety-nine pts were enrolled (Group 1: 78, Group 2: 21). Pts had a median age of 56/52 years (Group 1/2); 51%/33% had visceral metastases; 59%/43% were stage IV at initial diagnosis; 36%/33% were fully employed. In each group, 95% (78 pts and 20 pts, respectively) completed the 6-cycle observation period. In the overall population for each group, GHS was maintained across the observation period. Based on the analysis, treatment cycle demonstrated an association with GHS change from baseline score in early cycles (Cycle 2: mean change=4.79, 95%CI 0.93-8.65,; Cycle 3: mean change=6.53, 95%CI 2.75-10.31, p=0.001). Later cycles 4-6 continued to show a trend toward improvement in QOL; however these were less prominent. Additional trends included that CDK4/6i combination treatment (mean change=3.02, 95%CI -4.04- 10.07), first-line treatment (f mean change=2.87, 95%CI -4.18-9.93), and part-time employment (mean change=3.82, 95%CI -3.68- 11.32), which all showed improvement towards GHS from baseline; whereas, stage IV/other (mean change=-2.45, 95%CI -8.58- 3.65) and dose modification (mean change=-2.06, 95%CI -6.02-1.90) trended towards GHS decrease from baseline. Notably, by cycle 4, 91 pts remained on study (Group 1: 73, Group 2: 18). Conclusion: In this Japanese cohort, a gradual improvement in HRQoL was observed in the initial cycles of PAL+ET and ET alone. Although this is a small cohort of pts, our exploratory data provide an initial hypothesis around which pts may experience a benefit/detriment in HRQoL. Further investigation is warranted. (NCT04736576) Citation Format: Shigehira Saji, Mari Oba, Aya Ueda, Kaori Terata, Mihoko Doi, Shigenori Nagai, Masaya Hattori, Kenichi Watanabe, Nobuko Tamura, Manabu Futamura, Kei Koizumi, Naoki Niikura, Tempei Miyaji, Yasuaki Muramatsu, Linghua Xu, Asuka Matsui, Norikazu Masuda, Hiroko Bando. Potential risk factors for health-related quality of life (HRQoL) in palbociclib (PAL) plus endocrine therapy (ET) and ET alone patients with HR+/HER2- advanced breast cancer (ABC): exploratory analysis from 6-month longitudinal study (JBCRG-26) [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P4-10-03.

Abstract Background: Palbociclib (PAL) in combination with endocrine therapy (ET) has been approved for hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) advanced/metastatic breast cancer (MBC) since February 2025. Despite extensive real-world data in a variety of populations, little is known about the use and effectiveness of PAL combination in MBC patients living in disadvantaged neighborhoods. The current study aimed to compare overall survival (OS) and real-world progression-free survival (rwPFS) of first-line PAL plus an aromatase inhibitor (AI) vs AI alone in HR+/HER2 MBC patients living in disadvantaged neighborhoods in the US. Methods: This is a retrospective observational study of HR+/HER2- MBC patients in the Flatiron Health longitudinal database. The database contains electronic health records from >280 cancer clinics, representing >3 million actively treated cancer patients in the US. Patients were included in this analysis if they had HR+/HER2- MBC, were ≥18 years, started PAL + AI as first-line therapy between February 2015 and June 2022 (index period), and lived in disadvantaged neighborhoods. Neighborhood disadvantage was measured with the Yost index, a composite measure of neighborhood social economic status. The Yost index score ranges from 1 (the first quintile) to 5 (the fifth quintile), with higher scores indicating higher socioeconomic status of the neighborhoods. Neighborhood disadvantage was defined as a Yost Index score of 1-2. Patients were retrospectively assessed from start of PAL+AI to December 2022 (data cutoff date), death, or last medical activity, whichever came first. OS was defined as months from start of PAL+AI to death. rwPFS was defined as months from start of PAL+AI to death or disease progression, evaluated based on clinical assessment or radiographic scan/biopsy. Stabilized inverse probability of treatment weight (sIPTW) was used to balance baseline demographics and clinical characteristics. 1:1 propensity score matching (PSM) was performed as sensitivity analysis. Results: Of the 723 patients who were eligible for the analysis, 394 and 329 patients received PAL+AI and AI, respectively. Median follow-up was 27.2 months for PAL+AI and 25.7 months for AI treated patients. Compared with AI group, PAL+AI group was younger (median age 66.0 vs 69.0 years) and had higher proportions of de novo MBC (39.9% vs 24.0%) and lung/liver metastases (32.0% vs 19.8%). After sIPTW, baseline demographic and clinical characteristics were generally well balanced between PAL+AI and AI groups. After sIPTW, median OS was 57.1 (95%CI=47.2-70.8) months in PAL+AI group vs 38.2 (95%CI=29.6-48.0) months in AI group (HR=0.70, 95%CI=0.55-0.90, p =0.0053). Median rwPFS was 19.1 (95%CI = 15.8 – 24.2) months in PAL+AI group and 14.0 (95%CI=10.7-19.7) months in AI group (HR=0.66, 95%CI=0.52-0.84, p =0.0007). Sensitivity analysis with 1:1 PSM showed consistent results. Conclusions: This real-world data analysis demonstrated that first-line palbociclib plus AI was associated with prolonged OS and rwPFS in HR+/HER2- MBC patients living in disadvantaged neighborhoods. These findings support use of first-line palbociclib in combination with endocrine therapy in this population. Citation Format: Filipa Lynce, Xianchen Liu, Benjamin Li, Lynn McRoy, Connie Chen, Raymond Liu, Hope S. Rugo. Real-world effectiveness of palbociclib plus an aromatase inhibitor in HR+/HER2- MBC patients living in disadvantaged neighborhoods [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P4-12-04.

Abstract Background: Treatment for HR+/HER2-0 or HER2-low (Immunohistochemistry (IHC) 1+ or 2+/in situ hybridization, ISH-negative) ABC pts after ET and CDK4/6i depends on disease dynamics, prior chemotherapy (CT), performance status and the presence of actionable genomic alterations. Currently, trastuzumab deruxtecan is approved for HER2-low ABC after ≥1 line of CT, but is not reimbursed in Poland. Methods: We retrospectively analyzed treatment outcomes of HR+/HER2-0 or HER2-low ABC pts after progression on ET and CDK4/6: palbociclib (PAL), ribociclib (RIB) or abemaciclib (ABM). We analyzed second progression-free survival (PFS2), overall survival (OS) and duration of the subsequent line treatment after ET/CDK4/6i (DoT). Results: A total of 472 pts (PAL=127; RIB=222; ABM=78) from 12 Polish cancer centers treated between Sep 2017 and Dec 2023 were analyzed. Median follow-up was 33.3 (95%CI 31.2 to 36.3) months (m). Mean age was 59.8 ± 12.4 years. 200 patients (42%) had visceral and 358 (76%) bone metastases. 296 (63%) and 176 (37%) received CDK4/6i with aromatase inhibitor (AI) and fulvestrant (FUL), respectively. HER2 IHC: 0, 1+, 2+/ISH-negative subsets were:228 (48%), 153 (32%), 78 (17%), 13 (2.8%), respectively. PCT included fulvestrant 103 (22%), capecitabine 88 (19%), taxane 51 (11%), anthracycline 47 (10%), vinorelbine 43 (9.1%), anthracycline and cyclophosphamide 33 (7%), aromatase inhibitor 29 (6.1%), platinum compounds 24 (5.1%), alpelisib and fulvestrant 18 (3.8%), and other 36 (7.7%). Median DoT for HER2 0 and HER2 low was 4.2 (3.7-5.6) and 4.9 (4.1-6.0) m, respectively, HR= 0.79 (95%CI: 0.64-0.97), p=0.026; PFS2: 18 (15-20) and 20 m (18-23), HR=0.81 (0.65-0.99), p=0.042; OS: 26 (23-31) and 35 (30-39), HR=0.71 (0.55-0.91), p=0.007. Conclusions: HR+/HER2-negative ABC constitutes a heterogeneous population that vary in prognosis and sensitivity to systemic treatments. Compared to HER2-0, HER2-low subgroup has better outcomes following ET/CDK4/6i therapy. The outcomes of PTC and prognostic significance of the HER2-ultralow subtype warrants evaluation. Citation Format: Aleksandra Lacko, Katarzyna Pogoda, Katarzyna Soter, Aleksandra Grela-Wojewoda, Jolanta Smok-Kalwat, Karolina Winsko-Szczęsnowicz, Iwona Danielewicz, Joanna Streb, Agnieszka Kowalewska-Felczak, Bartosz Szymanowski, Tomasz Lewandowski, Joanna Kiszka, Ewa Kalinka, Anna Bałata, Magdalena Łoboza, Ewa Kustra, Anna Koriat-Błońska, Justyna Żubrowska, Aleksandra Łacko, Marek Ziobro, Bogumila Czartoryska-Arlukowicz, Michał Jurczyk, Grzegorz Kade, Rodryg Ramlau, Jacek Jassem, Michał Bieńkowski, Renata Duchnowska. Real-world outcomes of physician’s choice treatment (PCT) for hormone receptor-positive (HR+)/HER2-0 and HER2-low advanced breast cancer (ABC) patients (pts) after endocrine therapy (ET) and CDK4/6 inhibitors (CDK4/6i) [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P1-10-13.

1004 Background: INAVO, a highly potent and selective PI3Kα inhibitor that also promotes degradation of mutated p110α, is approved by the FDA in combination with PALBO + fulvestrant (FULV) for PIK3CA -mutated, HR+, HER2–, endocrine-resistant advanced BC. HG is a common on-target side effect of PI3K inhibitors. There are limited data for PI3K inhibitors in prediabetic/obese pts. Data from prediabetic/obese pts with HR+, HER2– LA/mBC treated with INAVO from a Phase I/Ib study (GO39374; NCT03006172) are reported here. Methods: Adults ≥ 18 years of age received INAVO alone (Arm A), + letrozole (LET) + PALBO (Arm B), + LET (Arm C), + FULV (Arm D), + FULV + PALBO (Arm E), or + FULV + PALBO + primary prophylactic metformin (Arm F). Data are reported across all arms unless indicated. Pts with baseline risk factors for HG were defined by HbA 1c ≥5.7%, fasting blood glucose ≥ 100 mg/dL, or body mass index ≥ 30 kg/m 2 . Adverse events (AEs) were reported using NCI-CTCAE v4, which utilizes fasting laboratory glucose values for HG severity grading, rather than clinical interventions used in v5. Results: Clinical cut-off was Jan 1, 2024. From190 pts treated, 110 (57.9%) were prediabetic/obese; their median time on INAVO was 222 days (range, 7 to 2,152) and mean cumulative dose intensity was 91.8%. Most prediabetic/obese pts discontinued INAVO due to progressive disease (82 [74.5%]); six (5.5%) discontinued INAVO due to an AE (one due to HG). HG was reported in 80.9% of prediabetic/obese pts (grade 3–4: 34.5%). In pts with two risk factors, 87.9% reported HG (grade 3–4: 39.4%). Among pts with HG, median time to onset was 14 days (range, 1 to 1,674) and 86.0% of events resolved by clinical cut-off. Median time to improvement or resolution of first worst grade ≥ 2 event was 8 days (range, 1 to 64). INAVO dose interruptions, reductions, and discontinuations due to HG were reported in 41.8%, 13.6%, and 0.9% of pts, respectively. The most common anti-HG medications were metformin (52.7%; biguanide; concomitant use in Arm F excluded), empagliflozin (25.5%; SGLT-2 inhibitor), sitagliptin (22.7%; DPP-4 inhibitor), and pioglitazone (13.6%; thiazolidinedione); insulin was used in 8.2% of pts. Median time to metformin start (excluding Arm F) was 14 days (range, 1 to 1,710); the median start dose was 1,000 mg total daily; and the highest daily start dose was 2,000 mg. More than one anti-HG medication was often needed. Conclusions: A high proportion of prediabetic/obese pts were included in GO39374. In most of these pts, HG was manageable with dose interruptions and oral anti-HG medications, most commonly metformin. Data support the use of INAVO in prediabetic/obese pts; further investigation of INAVO in pts with diabetes is warranted. Clinical trial information: NCT03006172 .