Neoadjuvant letrozole and palbociclib in patients with HR-positive/HER2-negative early breast cancer and Oncotype DX Recurrence Score ≥18: DxCARTES study.

BACKGROUND: The effect of the addition of cyclin-dependent kinases 4 and 6 inhibitors to endocrine therapy in terms of molecular downstaging remains undetermined. Switching from a high-risk to a low risk Recurrence Score (RS) group could provide useful information to identify patients who might not require chemotherapy. The purpose of this study was to assess the biological and clinical activity of letrozole plus palbociclib as neoadjuvant treatment for patients with hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative early breast cancer with an initial Oncotype DX RS ≥18. PATIENTS AND METHODS: Participants were women aged ≥18 years with HR-positive/HER2-negative, Ki67 ≥ 20%, stage II-IIIB early breast cancer with a baseline RS ≥18. Eligible patients with a pretreatment RS 18-25 (cohort A) and 26-100 (cohort B) received six 28-day cycles of letrozole (2.5 mg per day; plus goserelin if pre- or perimenopausal) plus palbociclib (125 mg per day; 3/1 schedule) before surgery. The primary endpoint for both cohorts was the proportion of patients who achieved an RS ≤25 at surgery or a pathological complete response (pCR). RESULTS: A total of 67 patients were enrolled, among which 65 were assessable for the primary endpoint (32 patients in cohort A and 33 in cohort B). At surgery, 22 (68.8%) patients in cohort A and 18 (54.5%) patients in cohort B had an RS ≤25 or a pCR [only 1 (3.0%) patient in cohort B], meeting the primary endpoint in cohort B (P < 0.01), but not in cohort A (P = 0.98). No new safety signals were identified. CONCLUSIONS: The efficacy of neoadjuvant treatment with letrozole plus palbociclib does not seem to depend on pretreatment RS for patients with RS ≥18. However, around half of patients with HR-positive/HER2-negative early breast cancer with an RS 26-100 at baseline achieved molecular downstaging with this regimen.

Clinical characterization, prognostic, and predictive values of HER2-low in patients with early breast cancer in the PALLAS trial (ABCSG-42/AFT-05/BIG-14-13/PrE0109).

BACKGROUND: Bidirectional crosstalk between HER2 and estrogen receptor (ER) pathways may influence outcomes and the efficacy of endocrine therapy (ET). Low HER2 expression levels (HER2-low) have emerged as a predictive biomarker in patients with breast cancer (BC). METHODS: PALLAS is an open, international, phase 3 study evaluating the addition of palbociclib for 2 years to adjuvant ET in patients with stage II-III ER-positive/HER2-negative BC. To assess the impact of HER2 expression on patient outcomes in the phase III PALLAS trial, we analyzed (1) the association between rate of HER2-low with demographic and clinicopathological parameters, (2) the prognostic value of HER2-low status on invasive disease-free survival (iDFS), distant relapse-free survival (DRFS), and overall survival (OS) and (3) HER2 expression's value as a predictive biomarker of response to palbociclib. HER2-low was defined as HER2 immunohistochemistry (IHC) 1 + or IHC 2 + with negative in situ hybridization (ISH). All pathologic evaluation was performed locally. Prognostic and predictive power of HER2 were assessed with Cox models. RESULTS: From the original PALLAS intention-to-treat population (N = 5753), 5304 patients (92.2%) were included in this analysis. Among these, 2254 patients (42.5%) were classified as having HER2 IHC 0 (HER2-0), and 3050 (57.5%) as having HER2-low disease (1838 with IHC 1 + and 1212 with IHC 2 +). Median follow-up was 59.8 months. HER2-low prevalence varied significantly across 21 participating countries (range 16.7% to 75.6%; p < 0.001) and was more frequent in patients enrolled in North America (63.1%) than in Europe (53.4%) or other regions (53.4%) (p < 0.001). HER2 status was not significantly associated with iDFS in a multivariable Cox model (hazard ratio 0.93, 95% confidence interval 0.81 - 1.06). No significant interaction was observed between treatment arm and HER2 status for iDFS (p = 0.43). Similar results were obtained for DRFS and OS. CONCLUSIONS: In this large, prospective, global patient cohort, no differences were observed in clinical parameters, prognosis, or differential benefit from palbociclib between HER2-0 and HER2-low tumors. Significant geographic variability was observed in the prevalence of HER2-low status, suggesting a high degree of variation in pathologic assessment of HER2 expression without impact on outcomes.

Comparing Ribociclib versus Palbociclib as a Second Line Treatment in Combination with Fulvestrant in Metastatic Breast Cancer: A Randomised Clinical Trial.

AIM: Assessment of CBR, PFS, QOL and toxicity profile of palbociclib and ribociclib. METHODS: This is an interventional concurrent randomised phase III open label clinical trial. It took place at the Oncology Centre Mansoura University, Egypt from July 2022 till December 2023. Patients with pathologically proved ER+ HER2- metastatic breast cancer who either progressed on adjuvant hormonal or progressed on 1st line hormonal for metastatic disease. Patients in arm A received palbociclib 125 mg/day orally for 3 weeks and 1 week rest, plus fulvestrant. Patients in Arm B received ribociclib at a dose of 600 mg, administered orally once daily for 3 weeks and 1 week rest, plus fulvestrant. Pre- and peri-menopausal women received the LHRH agonist goserelin. Patients who lost their endorsement and were considered to be lost to follow up. Quality of life was analysed using the (EORTC) quality-of-life questionnaire (QLQ)-C30 V3.0. Patients were asked to complete the questionnaires at screening; at the 2nd and 6th month. Toxicity was assessed and graded using (CTCAE) v5.0. Patients were evaluated clinically for response and toxicity monthly and radiologically by CT and tumor markers/ 3 months. Treatment continued until objective Progressive Disease (PD), symptomatic deterioration, unacceptable toxicity or death. RESULTS: Both arms had similar baseline characteristics. There was no statistically significant difference regarding the CBR (58.6% for both arms at 6 months and 13.8% in the palbociclib VS 17.2% in the ribociclib arm at 12 months). The median PFS to the whole population was 13 months. COX multivariate analysis revealed that postmenopausal had 2.85 more likely to survive than premenopausal patients. Patients with ECOG performance status 2 and 3 are 0.13 and 0.39 less likely to survive compared to patients with PS 1. Dose reduction increased the likelihood of survival 3.36 compared with no dose reduction. The median PFS was 13.67 months in the palbociclib arm and 12.69 months in the ribociclib arm with no statistically significant difference. During follow up, there was statistically significant improvement in insomnia in both arms and constipation in the palbociclib arm alone. Comparing the two arms, no statistically significant deterioration in the QOL domains except in fatigue and financial difficulties, with more deterioration in the palbociclib arm. Regarding common toxicities there was no statistically significant difference between the 2 arms. CONCLUSIONS: Both Ribociclib and palbociclib have similar CBR, PFS and toxicity profile.

Absolute lymphocyte count predicts efficacy of palbociclib in patients with metastatic luminal breast cancer.

BACKGROUND: Absolute lymphocyte count (ALC) is a predictive and prognostic factor for various tumor types, including breast cancer. Palbociclib is a CDK4/6 inhibitor widely used for the treatment of metastatic estrogen receptor (ER)-positive, HER2-negative breast cancer. However, predictive biomarkers of the efficacy of palbociclib remain unelucidated. We conducted a retrospective study to examine the predictive value of the baseline ALC in patients treated with palbociclib. METHODS: The medical records of patients with ER-positive, HER2-negative breast cancer treated with palbociclib plus hormonal therapy between December 2017 and December 2021 were analyzed retrospectively. The cutoff value of ALC was set at 1800 cells/µL at the initiation of palbociclib treatment. The clinical benefit rate (CBR) was defined as the rate of complete or partial response or stable disease for at least 6 months. Progression-free survival (PFS) rates were estimated using the Kaplan-Meier method and compared using the log-rank test. Univariate and multivariate analyses were performed using Cox proportional hazards regression. RESULTS: All of the 202 patients were women, with a median age of 59 years and a performance status (PS) of ≤ 2. The median numbers of lines of chemotherapy and endocrine therapy before palbociclib treatment were 0 (range, 0-9) and 1 (range, 0-7), respectively. Fifty-one patients had liver metastases. Forty-six patients tested negative for progesterone receptor (PgR) expression. The median follow-up time was 9.1 months. The CBR was significantly higher in the ALC-high group than in the ALC-low group (79% vs. 60%; P = 0.018). The median PFS was significantly longer in the ALC-high group than in the ALC-low group (26.8 months vs. 8.4 moths, respectively; P = 0.000013). ALC, age, PS, PgR status, prior chemotherapy, prior endocrine therapy, and liver metastasis were entered into the multivariate analysis. ALC was identified as an independent factor for PFS (P = 0.00085), along with liver metastasis (P = 0.0020), PS (P = 0.026), and prior endocrine therapy (P = 0.019). CONCLUSION: ALC can serve as a predictor of palbociclib efficacy in patients with metastatic ER-positive, HER2-negative breast cancer.

Development and characterization of palbociclib-loaded PLGA nanobubbles for targeted cancer therapy.

OBJECTIVE: The objective of this study was to develop and optimize palbociclib-loaded nanobubbles for targeted breast cancer therapy. MATERIALS AND METHODS: Biocompatible poly(DL-lactide-co-glycolide) was used to create nanobubbles loaded with palbociclib. The formulation process was meticulously crafted using a three-level Box-Behnken design and a double emulsion solvent evaporation method to precisely tailor the nanobubbles' properties. RESULTS: The Derringer's desirability method optimized variables by transforming responses into a desirability scale, resulting in a global desirability value. Optimal settings, A: 526.97mg, B: 250mg,C: 2.0% w/v, D: 6101rpm, achieved a D value of 0.949. Palbociclib nanobubbles demonstrated a smaller particle size (31.78±2.12) than plain nanobubbles (38.56±3.56). PDI values indicated a uniform size distribution. The zeta potential remained consistent, with values of -31.34±3.36 for plain and -31.56±3.12 for drug-loaded nanobubbles. Encapsulation efficiency was 70.12%, highlighting effective drug encapsulation. Palbociclib release was significantly higher from nanobubbles in pH 7.4, especially with ultrasound, releasing almost 99.34% of the drug. Hemolytic activity assays confirmed safety for injection. Fluorescent intensity analysis revealed a two-fold increase in cellular uptake of palbociclib facilitated by ultrasound. The MTT assay demonstrated enhanced cytotoxicity of palbociclib-loaded nanobubbles, especially with ultrasound, emphasizing their potential for improved therapeutic efficacy. The IC50 values for palbociclib, without ultrasound, and with ultrasound were 98.3µM, 72.34µM, and 61.34µM, respectively. CONCLUSION: The significant findings of this study emphasize the potential of palbociclib-loaded nanobubbles as a promising therapeutic system for improved breast cancer treatment.

Exploring pharmacokinetic variability of palbociclib in HR+/HER2- metastatic breast cancer: a focus on age, renal function, and drug-gene interactions.

Palbociclib, an oral inhibitor of cyclin-dependent kinase 4 and 6, is approved for the treatment of metastatic breast cancer. This study investigated the influence of diverse clinical and biological factors-age, renal function, genetic variations, and concomitant medications (pharmacokinetic covariates)-on palbociclib pharmacokinetics. Employing a validated LC-MS/MS method, we analyzed the minimum plasma concentrations (Ctrough) of palbociclib in 68 women and determined the percentage deviations from the median Ctrough for each dosage group. Variations in a panel of absorption, distribution, metabolism, and excretion (ADME) genes were assessed using end-point allele-specific fluorescence detection and pyrosequencing. Two distinct patient cohorts were defined based on median values of age, creatinine, and eGFR, which exhibited statistically significant differences in percentage deviations (p = 0.0095, p = 0.0288, and p = 0.0005, respectively). Homozygous carriers of the PPARA variants displayed larger positive percentage deviations than the other group (p = 0.0292). Similarly, patients concurrently taking CYP3A and P-glycoprotein inhibitors alongside anticancer therapy exhibited significant variations (p = 0.0285 and p = 0.0334, respectively). Furthermore, exploring the drug-drug-gene interactions between inhibitors of CYP3A and P-glycoprotein with their respective genetic variants revealed two patient groups with statistically different percentage deviations (p = 0.0075, p = 0.0012, and p = 0.0191, respectively). These results could help address cases where pharmacokinetic covariates or subclinical conditions impair palbociclib adherence or response, aiming to offer tailored dosing strategies or monitoring for individual patients.

Mechanistic Regulation of Epidermal Growth Factor and Hormonal Receptors by Kinase Inhibitors and Organofluorines in Breast Cancer Therapy.

Differential expression patterns of growth factor (EGFR, HER-2) and hormonal (ER, PR) receptors in breast cancer (BC) remain crucial for evaluating and tailoring therapeutic interventions. This study investigates differential expression profiles of hormonal and growth factor receptors in BC patients and across age groups, major subclasses, disease stages and tumor histology and survival rates, the efficacy of emerging clinical trial drugs (Dabrafenib and Palbociclib) and elucidating their molecular interaction mechanisms for efficient therapeutic strategies. Gene and protein expression analysis in the normal vs BC and across age groups and major subclasses reveals divergent patterns as EGFR and HER-2 levels are reduced in tumors versus normal tissue, while ER and PR levels are higher, particularly in luminal subtypes. However, there was no significant difference in survival rates among high and low/medium expression levels of EGFR and PR receptors. Conversely, patients with high HER-2 and ER expression exhibited poorer survival rates compared to low or medium expression levels. The in vitro findings indicate that Dabrafenib exhibits greater effectiveness than Palbociclib in suppressing various BC cells such as MCF-7 (Luminal), MDA-MB-231 (Triple-Negative), SKBR-3 (HER-2 + ) proliferation, promoting cell death, (IC50 of Dab < Pal) at 24 and 48 h, ROS production, and reduced ER and PR, elevated HER-2 with no change in EGFR expression. Molecular simulation studies revealed Dabrafenib's thermodynamically stable interactions (ΔG), tighter binding, and less structural deviation in the order EGFR > HER-2 > ER > PR as compared to Palbociclib (HER-2 > ER > PR = EGFR). These results indicate that Dabrafenib, compared to Palbociclib, more effectively regulates breast cancer cell proliferation through specific interactions with hormonal and growth factor receptors towards a repurposing approach.

Palbociclib: Randomized Studies and Real-world Evidence as the Basis for Therapeutic Planning in Metastatic Breast Cancer.

Endocrine-based combination therapy with an inhibitor of the cyclin-dependent kinases 4 and 6 (CDK4/6 inhibitors) is currently the first-line therapy of choice for patients with hormone receptor-positive (HR+) and human epidermal growth factor receptor 2-negative (HER2-), locally advanced or metastatic breast cancer (mBC). The efficacy and safety of the treatment with palbociclib, the first CDK4/6 inhibitor approved for this indication, have been confirmed in large randomized controlled clinical trials (RCTs) with strictly defined patient cohorts. Since then, many relevant questions about CDK4/6 inhibition with palbociclib for mBC have been investigated in RCTs and real-world studies. Based on this evidence, palbociclib is widely used in clinical practice since many years because of its efficacy and good tolerability. The aim of this review is to summarize findings from RCTs and RWE considering clinically relevant aspects such as safety, tolerability, quality of life and efficacy with a focus on specific questions and patient characteristics. A critical discussion and review of the overall evidence for endocrine-based therapy with the CDK4/6 inhibitor palbociclib can contribute to support therapy decisions in daily clinical practice.

Patterns and outcomes in HR+/HER2- advanced/metastatic breast cancer patients in Brazil receiving palbociclib.

Aim: To outline the demographic and clinical features, treatment approaches and clinical outcomes of patients treated with palbociclib as the initial therapy for HR+/HER2- advanced or metastatic breast cancer (aBC/mBC) in private healthcare facilities in Brazil. Materials & methods: This study involved a retrospective review conducted from June 2022 to May 2023. Results: The study included 121 patients, with an average age of 54.4 years, and 82 (67.7%) were menopausal at the time of diagnosis. Of these, 51 patients (42.1%) were treated with palbociclib and fulvestrant, while 67 patients (55.8%) received palbociclib and aromatase inhibitors. Most patients (65.3%) did not need to adjust their doses. The progression-free survival rates were 78% at 6 months and 60% at 12 months. Overall survival rates were 86% at 6 months and 70% at 12 months. Conclusion: Palbociclib combinations show promising effectiveness in managing HR+/HER2- advanced or metastatic breast cancer.

Treatment & results in Brazilian women with advanced or metastatic breast cancer given palbociclibBreast cancer is a major health issue worldwide, and it is the most common cancer among women in Brazil, with death rates on the rise. A significant portion of breast cancer cases are hormone receptor-positive (HR+) and HER2-negative (HER2-), making targeted treatments essential. One such treatment is palbociclib, a medication that inhibits Cyclin-dependent kinase 4 and 6 (CDK4/6), enzymes important in cell division. Clinical trials such as PALOMA-1, PALOMA-2 and PALOMA-3 have shown that palbociclib can help patients with advanced or metastatic HR+/HER2- breast cancer live longer without their disease getting worse. Studies in real-world settings around the world have confirmed these benefits, evaluating how well the treatment works over time. Palbociclib was approved for use in Brazil in 2018. This study looks back at the records of women treated with palbociclib in private healthcare settings in the country. It aims to provide crucial information which can help guide future treatment decisions.

A systematic review of health-related quality of life outcomes in patients with advanced breast cancer treated with palbociclib.

Aim: To evaluate the impact of palbociclib treatment on health-related quality of life (HRQoL) in patients with hormone receptor-positive, human epidermal growth factor 2-negative advanced breast cancer (HR+/HER2- aBC) or metastatic breast cancer (mBC) in both the clinical and real-world setting. Materials & methods: A systematic literature review was conducted to identify clinical trials and real-world evidence studies up to June 2023 that reported HRQoL outcomes in patients with HR+/HER2- aBC or mBC treated with Palbociclib. Results: 15 unique studies reported across 35 records were identified. Of these, seven were randomized controlled trials (RCTs), three were single-arm clinical trials and five were real-world evidence (RWE) studies. HRQoL was generally found to be maintained in patients with HR+/HER2- aBC or mBC across RCTs, single-arm clinical trials and RWE studies. HRQoL measures across instruments, study types and line of therapy, were largely reported to be at least maintained if not improved from baseline among patients treated with palbociclib and were observed to be comparable or better in the palbociclib group versus monotherapy control arm in RCTs. Similar results were seen for treatment-related outcomes (e.g., sexual functioning, upset by hair loss, systemic therapy side effects etc.), and important individual patient outcomes, including pain, fatigue and physical functioning. Findings were also consistent across key clinical characteristics (visceral metastases, neutropenia), as well as patient populations often underrepresented in clinical trials (Asian patients, older adults). Conclusion: Overall, current evidence suggests that HRQoL is largely preserved with the addition of palbociclib to endocrine therapy in patients with HR+/HER2- aBC or mBC across study types and populations.

Multispectral and molecular simulation of the interaction of human α1-acid glycoprotein with palbociclib.

Palbociclib, a selective CDK4/6 inhibitor with potent anti-tumor effects, was investigated for its interaction with human α1-acid glycoprotein (HAG). Spectral analysis revealed that palbociclib forms a ground state complex with HAG, exhibiting binding constant (Kb) of 104 M-1 at the used temperature range. The interaction between the two was determined to be driven mainly by hydrogen bonding and hydrophobic forces. Multispectral studies indicated that the bound palbociclib altered the secondary structure of HAG and reduced polarity around Trp and Tyr amino acids. And, molecular docking and dynamics simulations verified the experimental findings. Finally, most of the metal ions present in plasma, such as K+, Cu2+, Ca2+, Mg2+, Ni2+, Fe3+, and Co2+, are detrimental to the binding of palbociclib to HAG, with the exception of Zn2+, which is favorable.

Pirfenidone inhibits CCL2-mediated Treg chemotaxis induced by palbociclib and fulvestrant in HR+/HER2- breast cancer.

In human epidermal growth factor receptor 2-negative (HR+/HER2-) breast cancer, the most prevalent subtype, the pathological complete response (pCR) rate after neoadjuvant chemotherapy is less than 18 %, and the survival of patients with advanced-stage disease is approximately 34 %, highlighting the critical demand for more potent therapies. Recent research has underscored the substantial therapeutic benefits of the combination of CDK4/6 inhibitors and fulvestrant (Ful) in managing HR+/HER2- breast cancer. These therapeutics not only curtail tumor proliferation but also alter the tumor immune microenvironment, suggesting novel avenues for immunotherapy for this breast cancer subtype. Flow cytometry, PCR, WB, and RNA-seq experiments revealed that the combination of the CDK4/6 inhibitor palbociclib (Pal) with Ful upregulated CCL2 in tumor cells by inducing the SASP and activating the MAPK signaling pathway. CCL2 attracts Tregs to the tumor microenvironment, where it exerts an immunosuppressive effect. By administering the CCL2 inhibitor pirfenidone, we inhibited these effects and enhanced the antitumor efficacy of Pal + Ful. Our research revealed an immunosuppressive effect of CDK4/6 inhibitors and fulvestrant and suggested that CCL2 inhibitors may be a viable approach for treating patients with advanced HR+/HER2- breast cancer.

Profiling the Cardiovascular Toxicities of CDK4/6 Inhibitors: A Real-World Pharmacovigilance Study.

Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors are approved for the treatment of human epidermal growth factor receptor 2 (HER-2)-negative, hormone receptor-positive breast cancer. The cardiovascular toxicity of CDK4/6 inhibitors is not well understood. This study aims to profile the cardiac events associated with CDK4/6 inhibitors. Reports from 2015Q1 to 2024Q1 were obtained from the FDA Adverse Event Reporting System (FAERS). Reports identifying palbociclib, ribociclib, and abemaciclib as the primary suspect were examined for cardiovascular toxicity, including hypertension, cardiac failure, cardiomyopathy, arrhythmia, myocardial infarction, and myocarditis. Signal detection was performed using the proportional reporting ratio (PRR), reporting odds ratio (ROR), and information component (IC). A total of 69,139 reports were analyzed. The median time to adverse events was 69 days (interquartile range [IQR], 18-260 days). Of these, 2065 reports documented cardiac adverse events. Ribociclib and QT prolongation were re-confirmed as a signal (PRR 8.43, ROR 8.65, IC025 2.86). Hypertension and cardiac failure were the most frequently reported cardiovascular toxicities. This study demonstrates that the use of CDK4/6 inhibitors is associated with cardiovascular adverse events, such as heart failure and hypertension. Further research is needed to understand the mechanisms and risk factors contributing to the cardiovascular toxicity of CDK4/6 inhibitors.

Potential association of SULT2A1 and ABCG2 variant alleles with increased risk for palbociclib toxicity.

Aim: This study evaluated associations between CYP3A4*22 and variants in other pharmacogenes (CYP3A5, SULT2A1, ABCB1, ABCG2, ERCC1) and the risk for palbociclib-associated toxicities.Materials & methods: Two hundred cancer patients who received standard-of-care palbociclib were genotyped and associations with toxicity were evaluated retrospectively.Results: No significant associations were found for CYP3A4*22, CYP3A5*3, ABCB1_rs1045642, ABCG2_rs2231142, ERCC1_rs3212986 and ERCC1_rs11615. Homozygous variant carriers of SULT2A1_rs182420 had higher incidence of dose modifications due to palbociclib toxicity (odds ratio [OR]: 4.334, 95% CI: 1.057-17.767, p = 0.042). ABCG2_rs2231137 variant carriers had borderline higher incidence of grade 3-4 neutropenia (OR: 4.14, 95% CI: 0.99-17.37, p = 0.052).Conclusion: Once validated, SULT2A1 and ABCG2 variants may be useful to individualize palbociclib dosing to minimize toxicities and improve treatment outcomes.

[Box: see text].

The antitumor activity of osimertinib plus palbociclib in non-small cell lung cancer patient-derived xenograft (PDX)/2D/3D culture models harboring EGFR amplification and CDKN2A/2B homozygous deletions.

Non-small cell lung cancer (NSCLC) patients without targetable driver mutation have limited treatment options. In this study, we aimed to explore a new therapeutic strategy by using established nine patient-derived xenograft (PDX) and two-dimensional (2D) /3D culture models with specific genetic alternations. The gene mutations and copy number aberrations were detected by next-generation sequencing and confirmed using polymerase chain reaction (PCR) followed by DNA sequencing, and genomic DNA quantitative PCR. Protein expression was evaluated by immunohistochemistry. Drug sensitivities of PDX/2D/3D models were evaluated by in vivo and in vitro antitumor assays. RNA interference was performed to silence gene expression. Our study found that 44.4 % (4/9) of cases had CDKN2A homozygous deletion (homdel), while 33.3 % (3/9) had CDKN2B homdel. Additionally, 22.2 % (2/9) had amplification (amp) in wildtype CDK4, 44.4 % (4/9) in CDK6, and 44.4 % (4/9) in EGFR. Among the cases, 77.8 % (7/9) lacked CDKN2A, and 33.3 % (3/9) had high CDK4, CDK6, and EGFR had high protein expression. Moreover, 33.3 % (3/9) had KRAS mutations, and 66.7 % (6/9) had TP53 mutations. Antitumor activity of osimertinib plus palbociclib was assessed in four PDX/2D/3D models, two of which had simultaneous EGFR amp and CDKN2A/2B homdel. The data showed that NSCLC with EGFR amp and CDKN2A/2B homdel were sensitive to combined drugs. Additional oncogenic KRAS mutation reduced the drug's antitumor effect. EGFR amp is responsible for osimertinib sensitivity. Osimertinib plus palbociclib effectively treat NSCLC with wildtype EGFR and CDK6 amp and CDKN2A/2B homdel in the absence of oncogenic KRAS mutation.

Comparative effectiveness analysis of survival with first-line palbociclib or ribociclib plus AI in HR + /HER2- advanced breast cancer (CEPRA study): preliminary analysis of real-world data from Thailand.

BACKGROUND: The current standard first-line treatment for hormone receptor-positive/human epidermal growth factor receptor 2 negative (HR + /HER2 -) advanced breast cancer (ABC) is a combination of aromatase inhibitor (AI) plus CDK4/6 inhibitors (CDK4/6i). Direct comparison trials of different CDK4/6i are scarce. This real-world study compared the effectiveness of first-line AI plus ribociclib versus palbociclib. METHODS: This multicenter retrospective cohort study, conducted in six cancer centers in Thailand, enrolled patients with HR + /HER2 - ABC treated with first-line AI, and either ribociclib or palbociclib. Propensity score matching (PSM) was performed. The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), overall response rate (ORR), time to chemotherapy (TTC), and adverse events. RESULTS: Of the 250 patients enrolled, 134 patients with ribociclib and 49 patients with palbociclib were captured after PSM. Baseline characteristics were well-balanced between groups. Median PFS in patients receiving ribociclib and palbociclib were 27.9 and 31.8 months, respectively (hazard ratio: 0.87; 0.55-1.37). The median OS in the AI + ribociclib arm was 48.7 months compared to 59.1 months in the AI + palbociclib arm (hazard ratio: 0.55; 0.29-1.05). The median TTC in the AI + palbociclib group was 56 months, but not reached in the AI + ribociclib group (p = 0.42). The ORR of AI + ribociclib and AI + palbociclib were comparable (40.5% vs. 53.6%, p = 0.29). Patients receiving palbociclib demonstrated a higher proportion of neutropenia compared to those receiving ribociclib, despite a similar dose reduction rate (p = 0.28). Hepatitis rate was similar between the ribociclib (21%) and palbociclib groups (22%). Additionally, a low incidence of QT prolongation was observed in both the ribociclib (5%) and palbociclib groups (4%). CONCLUSION: This preliminary analysis of a real-world study demonstrated the comparable effectiveness of ribociclib and palbociclib with AI as an initial therapy for HR + /HER2 - ABC. No statistically significant difference in PFS, OS, and TTC was found in patients treated with AI combined with palbociclib or ribociclib. Longer follow-up and further prospective randomized head-to-head studies are warranted.

Comparative cost-effectiveness analysis of CDK4/6 inhibitors in the first-line treatment of HR-positive and HER2-negative advanced breast cancer: a Markov's model-based evaluation.

Introduction: CDK4/6 inhibitors are the first-line treatment for HR+/HER2- advanced breast cancer. Despite their clinical benefit, they can increase healthcare expenditure. To date, there is no thorough comparison among the three approved CDK4/6 inhibitors in terms of their cost-effectiveness. Objective: To investigate and compare the cost-effectiveness of CDK4/6 inhibitors in combination with letrozole as a first-line treatment for advanced breast cancer with hormonal-receptor-positivity and HER-2-negativity versus one another and versus letrozole monotherapy. Methods: A 10-year within-cycle-corrected Markov's model was employed from the healthcare payer perspective. Costs were obtained from the National Center for Cancer Care and Research (NCCCR) in Qatar. Utilities and transition probabilities were calculated from published landmark trials of PALOMA-2, MONALEESA-2, MONARCH-3, PO25, and other relevant literature. Costs, measured in Qatari Riyal (QAR), and effectiveness, measured in quality-adjusted-life-years (QALYs), were incremented and the incremental cost-effectiveness ratio (ICER) was compared to a willingness-to-pay threshold (WTP) of 1.5 Qatari GDP (448,758 QAR). A deterministic sensitivity analysis was implemented to account for uncertainties. Results: Ribociclib was the most effective option, generating 4.420 QALYs, followed by palbociclib (4.406 QALYs), abemaciclib (4.220 QALYs), then letrozole monotherapy (2.093 QALYs). As for cost-effectiveness, ribociclib dominated palbociclib. However, it was not cost-effective compared to abemaciclib (ICER=1,588,545 QAR/QALY). Ribociclib remained dominant over palbociclib with all uncertainties. The base-case conclusion of ribociclib versus abemaciclib remained robust over all uncertainties. Conclusion: From the healthcare payer perspective in Qatar, ribociclib is the most effective CDK4/6 inhibitor. It was dominant over palbociclib in terms of cost-effectiveness; however, it was not cost-effective compared to abemaciclib at current prices.

Palbociclib in HR-Positive, HER2-Negative Advanced/Metastatic Breast Cancer: A Systematic Scoping Review of Real-World Evidence from Countries Outside of Western Regions that Are Underrepresented in Clinical Trials.

INTRODUCTION: Limited awareness exists regarding real-world data (RWD) for palbociclib in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced/metastatic breast cancer in populations from certain countries outside of Western regions. METHODS: A systematic scoping review was conducted using PubMed and Embase to evaluate RWD for palbociclib from countries outside of Western regions that are underrepresented in clinical trials. Search criteria were aligned with our research question for relevant English-language publications, without restrictions on publication date, followed by Phase 1 (title and abstract) and Phase 2 (full-text) screening of retrieved citations as per Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Data analyses of eligible studies were done separately for abstracts and full-text publications to enhance the precision and reliability of the results. RESULTS: Database search yielded 1485 non-duplicate records, 46 qualified for inclusion, of which 47.8% were published as full text. The analysis of outcomes, based exclusively on full-text publications that collectively included 2048 patients treated with palbociclib, revealed the median progression-free survival (PFS) of 20.2-36.7 months, overall survival (OS) of 39.9 months (reported in one publication) and objective response rate (ORR) of 45.3-80.0% with first-line treatment. In ≥ second line, the median PFS, OS and ORR ranged from 7.0 to 24.2 months, 11 to 19.6 months, and 13.9% to 47.9%, respectively. The safety profile of palbociclib was similar to that reported in pivotal clinical studies, and no new safety concerns were identified. CONCLUSIONS: A comprehensive volume of evidence demonstrates that palbociclib's effectiveness and safety profile in real-world settings align with those observed in clinical trials, offering valuable insights for clinical decision-making in countries outside of Western regions underrepresented in clinical trials.

Comparative analysis of adverse events associated with CDK4/6 inhibitors based on FDA's adverse event reporting system: a case control pharmacovigilance study.

BACKGROUND: Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors marked a milestone in the breast cancer treatment. Due to the potential impact of adverse effects on treatment decisions and patient outcomes, careful consideration of the varying toxicities of CDK4/6 inhibitors is crucial, as three inhibitors-palbociclib, abemaciclib, and ribociclib-have been approved with differences in adverse event profiles. However, limitations in clinical trials call for urgent real-world safety studies to evaluate and compare the risk of adverse events (AEs) among these CDK4/6 inhibitors. Therefore, this study aimed to analyze AEs of CDK4/6 inhibitors and provide insights for clinical drug selection, using real world database. METHODS: The AEs of CDK4/6 inhibitors in the FDA Adverse Event Reporting System (2015-2022) were analyzed. Four disproportionality methods were used to detect safety signals: reporting odds ratio (ROR), proportional reporting ratio, Bayesian Confidence Neural Network Propagation, and Multi-Item Gamma Poisson Shrinker. Venn analysis was used to compare and select common and specific AEs. RESULTS: This study included 73,042 patients treated with palbociclib, 25,142 with ribociclib, and 7563 with abemaciclib. All three inhibitors had 27 common AEs. Palbociclib exhibited the highest ROR for hematologic toxicities, while ribociclib showed the highest ROR for macrocytosis, nail disorders, and hepatic lesions. Abemaciclib displayed the highest ROR for mucosal toxicity. Common signals for both palbociclib and ribociclib included hematologic toxicities, decreased immune responsiveness, and aphthous ulcers. Myelosuppression, oral pain, and pseudocirrhosis were common signals for palbociclib and abemaciclib. Anemia, hepatotoxicity, and pneumonitis were observed as common signals for ribociclib and abemaciclib. Furthermore, specific AEs associated with palbociclib included fatigue, alopecia, and stomatitis. For ribociclib, specific AEs included electrocardiogram QT prolongation, thrombocytopenia, and decreased hemoglobin. Abemaciclib was specifically linked to diarrhea, vomiting, and interstitial lung disease. CONCLUSION: Our analysis revealed that palbociclib showed a higher risk of hematologic toxicity. Ribociclib showed higher risks of hepatotoxicity, nephrotoxicity, and QT prolongation. Abemaciclib showed higher risks of hepatotoxicity, gastrointestinal effects, interstitial lung disease, and thrombosis. These findings provide valuable insights for CDK4/6 inhibitor selection.

PLGA Nanoplatform for the Hypoxic Tumor Delivery: Folate Targeting, Therapy, and Ultrasound/Photoacoustic Imaging.

Effective targeting of breast tumors is critical for improving therapeutic outcomes in breast cancer treatment. Additionally, hypoxic breast cancers are difficult to treat due to resistance toward chemotherapeutics, poor vascularity, and enhanced angiogenesis, which complicate effective drug delivery and therapeutic response. Addressing this formidable challenge requires designing a drug delivery system capable of targeted delivery of the anticancer agent, inhibition of efflux pump, and suppression of the tumor angiogenesis. Here, we have introduced Palbociclib (PCB)-loaded PLGA nanoparticles (NPs) consisting of chitosan-folate (CS-FOL) for folate receptor-targeted breast cancer therapy. The developed NPs were below 219 nm with a smooth, spherical surface shape. The entrapment efficiencies of NPs were achieved up to 85.78 ± 1.8%. Targeted NPs demonstrated faster drug release at pH 5.5, which potentiated the therapeutic efficacy of NPs due to the acidic microenvironment of breast cancer. In vitro cellular uptake study in MCF-7 cells confirmed the receptor-mediated endocytosis of targeted NPs. In vivo ultrasound and photoacoustic imaging studies on rats with hypoxic breast cancer showed that targeted NPs significantly reduced tumor growth and hypoxic tumor volume, and suppressed angiogenesis.