Treatment Of Advanced Breast Cancer Research Articles

8595 Brain Penetration Impedes SERD Efficacy in Breast Cancer Pre-clinical Models

Abstract Disclosure: S.E. Wardell: None. B. Chakraborty: None. S. Artham: None. M.A. Newlin: None. M. Kirkland: None. C. Chang: None. D.P. McDonnell: None. Most breast cancers express the estrogen receptor (ER, ESR1), and agents that target ER remain the cornerstone of interventions used to treat this disease at all stages. Aromatase inhibitors (AI), which block estrogen synthesis, and the selective ER downregulator (SERD) fulvestrant were developed with the goal of achieving absolute inhibition of ER signaling in tumors. However, it has been assumed that the clinical efficacy (and utility) of fulvestrant is somewhat limited by its poor pharmaceutical properties and the requirement that it be administered by intramuscular injection. This, together with the observation that the activating ESR1 mutations selected for during AI treatment are not effectively inhibited by fulvestrant, encouraged the development of new classes of SERDs that achieve sufficient exposure to saturate and degrade ER in tumors. The recent approval of the second-generation SERD elacestrant for the treatment of breast cancers harboring ESR1 mutations was a major advance in approaches to target ER in advanced breast cancer. Several additional oral SERDs have been developed and evaluated as potential treatments for advanced metastatic breast cancer. Despite showing substantial efficacy in pre-clinical assays that assess ER downregulation and gene transcription, and notably equivalent antitumor activities in cell line derived and PDX tumors in immunocompromised mice, the clinical development of the majority of these SERDs has been discontinued for lack of efficacy. In reviewing the available clinical data across many SERD programs, we noted that some drugs demonstrated a paradoxical, non-linear response curve with higher doses exhibiting less efficacy than lower doses. Probing this pharmacology in animal models we determined that the ability of SERDs to cross the blood brain barrier and attenuate ER signaling in the hypothalamus was a key differentiator of SERDs. In validated syngeneic models of breast cancer, we observed doses of fulvestrant having confirmed brain exposure stimulated tumor growth independent of tumor ER-status. We evaluated the ability of several next generation SERDs for their brain penetrance and demonstrated that SERD presence in the brain was associated with a stimulatory effect on tumor growth. Interestingly, administration of a low dose of 17b-estradiol (E2) together with a brain excluded SERD further repressed tumor growth, highlighting a potentially beneficial anti-tumor role for estrogen signaling in the brain. Furthermore, combination of a brain excluded SERM with E2 also resulted in increased tumor growth repression; thus, ER downregulation is dispensable for the cooperative activity observed for estrogens administered together with a peripheral ER antagonist. These data suggest that differences in tissue pharmacology, as opposed to differences in ability to degrade ER, is likely to be a major differentiator of ER modulators. Presentation: 6/3/2024

Effectiveness of combined targeted and hormonal therapies for post-menopausal women with hormone receptor-positive and HER2-negative advanced breast cancer: A systematic review and meta-analysis of RCTs.

we aim to synthesize available evidence on the effectiveness of hormonal plus targeted therapies for post-menopausal women with hormone receptor-positive and HER2-negative advanced breast cancer. We searched the following databases: Medline, PubMed, Cochrane Library, CINAHL, Web of Science, Scopus, and African Journal. Only studies that investigated the effectiveness of hormonal therapy combined with targeted therapy for HR+/HER2- advanced breast cancer treatment were included. The outcomes were progression-free survival (PFS), overall survival (OS) and objective response rate (ORR). A random-effect meta-analysis model was employed. Statistical analysis was performed using Comprehensive Meta-analysis version 3. 24 studies were included in the meta-analysis with an overall sample size of 7635. Median PFS, OS and ORR were found to be significantly increased in the combination group compared to hormonal monotherapy [SMD = 6.072 (95% CI = 3.785-8.360), p < 0.001], [SMD = 1.614 (95% CI = 0.139-3.089), p = 0.032] and [OR = 1.584 (CI 1.134-2.213), p = 0.007] respectively. Subgroup analysis showed a significant difference in PFS and ORR between patients who received "hormonal therapy + CDK4/6 inhibitors" vs hormonal therapy only [SMD = 6.015 (CI 3.069-8.960), p < 0.001], (OR = 1.828 (CI 1.030-3.243), p = 0.039] respectively. Compared with hormonal monotherapy, targeted plus hormonal therapy significantly improves PFS, OS and ORR in postmenopausal women with HR+/HER2- advanced breast cancer.

Determining Clinicopathologic Factors That Influence Treatment in Advanced Breast Cancer in Argentina After CDK4/6 Inhibitors.

The optimal treatment sequence for hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC) after progression on first-line cyclin-dependent kinase 4/6 inhibitor (CDKi) and endocrine therapy is unclear. Clinical and biological factors influencing treatment choices and outcomes in the second-line setting need to be elucidated. This is a retrospective analysis of a real-world cohort including patients with HR+/HER2- ABC who received CDKi and endocrine therapy in the first-line setting and progressed, requiring second-line treatment. Clinical and biological factors were analyzed to evaluate their association with daily treatment decisions and the prognostic role of progression-free survival (PFS) in the second-line setting. Two hundred thirty-five patients were included. Second-line treatments were hormone therapy (HT) based in 60% and chemotherapy based in 40% of patients. The second-line median PFS was 6.6 months, with no difference between treatment types. In multivariable analysis, postmenopausal status, lower Ki-67 expression, and non-de novo stage IV disease were associated with improved second-line (2L) PFS. Menopausal status significantly interacted with treatment type, with reduced PFS in premenopausal patients receiving HT-based treatments (4.7 v 8.7 months, P = .00045). In our study, treatment decisions reflected the current algorithm incorporated in our clinical guidelines, and prior treatment response was the most relevant factor to determine 2L treatment decision. Menopausal status interacted with the subsequent therapy efficacy in this setting. Hence, we consider that menopausal status should be routinely evaluated in the subgroup analysis of clinical trials.

Advancements in Immunotherapy for Breast Cancer: Mechanisms, Efficacy, and Future Directions.

Breast cancer is a major global health challenge characterized by its diverse biological behavior and varying treatment responses. Traditional therapies, including surgery, radiation, chemotherapy, hormonal therapy, and targeted therapy, have significantly advanced breast cancer treatment but are often limited by issues such as resistance, side effects, and variable efficacy. Immunotherapy has emerged as a transformative approach, leveraging the body's immune system to target and eliminate cancer cells. This review provides a comprehensive overview of recent advancements in immunotherapy for breast cancer, detailing the mechanisms of various therapeutic strategies, including checkpoint inhibitors, monoclonal antibodies, cancer vaccines, adoptive cell therapy, and oncolytic virus therapy. We evaluate the efficacy of these approaches in different stages of breast cancer, highlighting successes and challenges encountered in clinical settings. The review also addresses the current limitations of immunotherapy, such as treatment-related adverse effects, resistance mechanisms, and issues of cost and accessibility. We discuss promising future directions, including emerging targets, combination therapies, and personalized medicine approaches. By integrating recent research and clinical trial data, this review aims to elucidate the potential of immunotherapy to revolutionize breast cancer treatment, offering insights into its future role in improving patient outcomes and shaping the landscape of oncological care.

AI-based big data analysis of user-generated content to understand adherence in oral hormone receptor-positive advanced breast cancer treatment: A literature review and patient-centered approach using natural language processing

AI-based big data analysis of user-generated content to understand adherence in oral hormone receptor-positive advanced breast cancer treatment: A literature review and patient-centered approach using natural language processing

Targeting ITGβ3 to Overcome Trastuzumab Resistance through Epithelial-Mesenchymal Transition Regulation in HER2-Positive Breast Cancer.

HER2-positive breast cancer, representing 15-20% of all breast cancer cases, often develops resistance to the HER2-targeted therapy trastuzumab. Unfortunately, effective treatments for advanced HER2-positive breast cancer remain scarce. This study aims to investigate the roles of ITGβ3, and Hedgehog signaling in trastuzumab resistance and explore the potential of combining trastuzumab with cilengitide as a therapeutic strategy. Quantitative gene expression analysis was performed to assess the transcription of EMT (epithelial-mesenchymal transition) markers Slug, Snail, Twist2, and Zeb1 in trastuzumab-resistant HER2-positive breast cancer cells. The effects of ITGβ3 and Hedgehog signaling were investigated. Additionally, the combination therapy of trastuzumab and cilengitide was evaluated. Acquired trastuzumab resistance induced the transcription of Slug, Snail, Twist2, and Zeb1, indicating increased EMT. This increased EMT was mediated by ITGB3 and Hedgehog signaling. ITGβ3 regulated both the Hedgehog pathway and EMT, with the latter being independent of the Hedgehog pathway. The combination of trastuzumab and cilengitide showed a synergistic effect, reducing both EMT and Hedgehog pathway activity. Targeting ITGβ3 with cilengitide, combined with trastuzumab, effectively suppresses the Hedgehog pathway and EMT, offering a potential strategy to overcome trastuzumab resistance and improve outcomes for HER2-positive breast cancer patients.

A comparative study of sericin and gluten for magnetic nanoparticle-mediated drug delivery to breast cancer cell lines

With breast cancer emerging as a pressing global health challenge, characterized by escalating incidence rates and geographical disparities, there is a critical need for innovative therapeutic strategies. This comprehensive research navigates the landscape of nanomedicine, specifically focusing on the potential of magnetic nanoparticles (MNPs), with magnetite (Fe3O4) taking center stage. MNPs, encapsulated in biocompatible polymers like silica known as magnetic silica nanoparticles (MSN), are augmented with phosphotungstate (PTA) for enhanced chemodynamic therapy (CDT). PTA is recognized for its dual role as a natural chelator and electron shuttle, expediting electron transfer from ferric (Fe3+) to ferrous (Fe2+) ions within nanoparticles. Additionally, protein-based charge-reversal nanocarriers like silk sericin and gluten are introduced to encapsulate (MSN-PTA) nanoparticles, offering a dynamic facet to drug delivery systems for potential revolutionization of breast cancer therapy. This study successfully formulates and characterizes protein-coated nanocapsules, specifically MSN-PTA-SER, and MSN-PTA-GLU, with optimal physicochemical attributes for drug delivery applications. The careful optimization of sericin and gluten concentrations results in finely tuned nanoparticles, showcasing uniform size, enhanced negative zeta potential, and remarkable stability. Various analyses, from Dynamic Light Scattering (DLS) and scanning electron microscopy (SEM) to transmission electron microscopy (TEM), Fourier Transform Infrared Spectroscopy (FTIR), X-Ray diffraction analysis (XRD), and Thermogravimetric analysis (TGA), provide insights into structural integrity and surface modifications. Vibrating Sample Magnetometer (VSM) analysis underscores superparamagnetic behavior, positioning these nanocapsules as promising candidates for targeted drug delivery. In vitro evaluations demonstrate dose-dependent inhibition of cell viability in MCF-7 and Zr-75–1 breast cancer cells, emphasizing the therapeutic potential of MSN-PTA-SER and MSN-PTA-GLU. The interplay of surface charge and pH-dependent cellular uptake highlights the robust stability and versatility of these nanocarriers in tumor microenvironment, paving the way for advancements in targeted drug delivery and personalized nanomedicine. This comparative analysis explores the suitability of silk sericin and gluten, unraveling a promising avenue for the development of advanced, targeted, and efficient breast cancer treatments.

Accuracy of MRI Versus PET/CT in the Prediction of Treatment Response to Neoadjuvant Chemotherapy in Breast Cancer.

Background Breast-conserving surgeries have significantly advanced breast cancer treatment, offering favorable oncological outcomes, enhanced cosmetic results, reduced postoperative morbidity, and better psychological acceptance compared to mastectomy. The introduction of neoadjuvant therapy has expanded the applicability of breast conservation surgery to include locally advanced tumors. Tumor response to neoadjuvant chemotherapy is evaluated using imaging modalities such as breast ultrasound, breast magnetic resonance imaging (MRI), and positron emission tomography/computed tomography (PET/CT). Accurate prediction of therapeutic response facilitates the planning of surgical and adjuvant treatments. This study aims to compare the diagnostic accuracy of MRI and PET/CT in predicting treatment response to neoadjuvant chemotherapy in breast cancer patients. Methods This retrospective study was conducted at a tertiary care center in Bahrain. A total of 138 patients with locally advanced breast cancer or human epidermal growth factor receptor-2 (HER2) positive, hormone receptor-negative cancers who underwent breast-conserving surgeries between June 2018 and December 2022 were included. The inclusion criteria focused on patients achieving a complete pathological responsefollowing neoadjuvant systemic therapy, ensuring a homogenous study population. Patients with hormone receptor-positive early breast cancers or metastatic tumors, ineligible for neoadjuvant chemotherapy, were excluded. Non-responders and partial responders were also excluded from the study. Statistical analysis was performed using IBM SPSS v26.0 (IBM Corp., Armonk, US). Response rates for the imaging modalities and histopathology results were assessed. Agreement between histology and imaging modalities was computed using kappa statistics. Diagnostic performance for predicting "no residual" disease was evaluated using the McNemar Test. All tests were two-tailed, with a p-value <0.05 considered statistically significant. Results The study included 138 patients, of whom 73 (52.9%) had an incomplete response or residual disease, while 65 (47.1%) had a complete response or no residual disease according to histology reports. There was slight agreement between post-neoadjuvant MRI and histology results (Cohen's kappa 0.172, p=0.010), while substantial agreement was observed between post-neoadjuvant PET/CT and histology results (Cohen's kappa 0.614, p=0.000). PET/CT demonstrated a higher sensitivity of 93.8% (p<0.001) and a specificity of 68.5%. Although MRI was more specific, the positive predictive value was comparable for both PET/CT and MRI. Conclusion PET/CT shows higher sensitivity and can serve as an early marker for predicting complete pathological response in post-neoadjuvant breast cancer patients. However, the prediction of residual disease is optimized by combining both MRI and PET/CT as diagnostic modalities.

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.

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. 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. 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. 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. 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.

Evaluating the simultaneous electrochemical determination of antineoplastic drugs using LaNiO3/g-C3N4@RGH nanocomposite material

A novel electrochemical sensor based on LaNiO3/g-C3N4@RGH nanocomposite material was developed to simultaneously determine Ribociclib (RIBO) and Alpelisib (ALPE). Ribociclib and Alpelisib are vital anticancer medications used in the treatment of advanced breast cancer. The sensor exhibited excellent electrocatalytic activity towards the oxidation of RIBO and ALPE, enabling their simultaneous detection. The fabricated sensor was characterized using various techniques, including energy dispersive X-ray (EDX), Fourier-transform infrared spectroscopy (FTIR), X-ray diffraction (XR), scanning electron microscopy (SEM), and X-ray photoelectron spectroscopy (XPS), which confirmed the successful synthesis of the LaNiO3/g-C3N4@RGH composite material. Electrochemical characterization revealed enhanced conductivity and lower resistance of the modified electrode compared to the bare electrode. The developed sensor exhibited high repeatability, reproducibility, stability, and selectivity toward RIBO detection. Furthermore, the sensor displayed high sensitivity with low detection limits of 0.88 nM for RIBO and 6.1 nM for ALPE, and linear ranges of 0.05–6.2 μM and 0.5–6.5 μM, respectively. The proposed electrochemical sensor offers a promising approach for simultaneously determining RIBO and ALPE in pharmaceutical formulations and biological samples with recovery data of 98.7–102.0 %, providing a valuable tool for anticancer drug analysis and clinical research.

Assesment of Safety Profile of Immunotherapeutic Agents other than Immune Checkpoint Inhibitors in Cancer Patients

Introduction: Immunotherapy is a form of oncologic treatment directed towards enhancing the host immune system against cancer. Immunotherapeutic agents were significantly associated with a higher risk of developing adverse effects in cancer patients. Bevacizumab was significantly associated with higher risk of developing venous thromboembolism, GI perforation such as bleeding and leukopenia in cancer patients. Trastuzumab has led to a significant improvement in the treatment of both advanced and early breast cancer by over expressing HER-2 receptors. It was associated with an important adverse effect, cardiotoxicity. Cetuximab and Panitumumab are monoclonal antibodies targeting the endothelial growth factor receptors (EGFR) currently used for systemic treatment of metastatic colorectal cancer in combination or alone have been reported to be able to induce skin toxicities. Nausea, diarrhea and rash were the most common adverse effects in Pertuzumab alone and Pertuzumab – based therapies. Pertuzumab also increases the risk of clinical heart failure, but not asymptomatic/minimally symptomatic left ventricular systolic dysfunction, in HER2-positive cancer patients. Materials and Methods: An ambispective observational single center study was conducted by collecting details of patients prescribed with Trastuzumab, Bevacizumab Pertuzumab, cetuximab and panitumumab. Retrospective study period of 5 years (2017 November to 2022 November) and Prospective study period of 6 months were conducted (December 2022 to May 2023). Patients of all age groups prescribed with immunotherapeutic agents other than immune checkpoint inhibitors was included and patients who were discharged against medical advice and incomplete data was excluded. Results: Majority of patients in our study were in age groups of 56-65 years with 38.5%. Among 65 patients, 4 of them reported with trastuzumab induced cardiotoxicity and 3 of the patients taking trastuzumab along with pertuzumab also reported with cardiotoxicity. Among 30 patients who were taking bevacizumab, one patient was reported with pneumonitis. We conducted a correlation analysis using chi-square test between study considered drugs and the reported adverse reactions. All of the patients prescribed with Trastuzumab + Pertuzumab were having ADR. Also, majority of the patients prescribed with Bevacizumab were not having ADR. Since the p-value of chi-square test was found to be &lt;0.001 so there exist a significant relation between drugs prescribed and ADR. Conclusion: We assessed the safety profile of immunotherapeutic agents other than immune check point inhibitors in cancer patients. We also correlated the study considered drugs and adverse drug reaction occurrence, there existed a significant correlation.

Capecitabine monotherapy as first-line treatment in advanced HER2-normal breast cancer - a nationwide, retrospective study.

The study utilized the Danish Breast Cancer Group (DBCG) database and was conducted retrospectively across all Danish oncology departments. Inclusion criteria were female patients, with HER2-normal advanced breast cancer treated with capecitabine monotherapy as the first-line treatment from 2010 to 2020. The primary endpoints were overall survival (OS) and progression-free survival (PFS). A total of 494 patients were included. Median OS was 16.4 months (95% confidence interval [CI]: 14.5-18.0), and median PFS was 6.0 months (95% CI: 5.3-6.7). Patients with estrogen receptor (ER)-positive disease had significantly longer OS (median: 22.8 vs. 10.5 months, p < 0.001) and PFS (median: 7.4 vs. 4.9 months, p = 0.003), when compared to ER-negative patients. Stratifying by age, patients under 45 years displayed a median PFS of 4.1 months, while those aged 45-70 years and over 70 years had median PFS of 5.7 and 7.2 months, respectively (p = 0.01). In this nationwide study, the efficacy of capecitabine as a first-line treatment for HER2-normal advanced breast cancer is consistent with other, mainly retrospective, studies. However, when assessed against contemporary and newer treatments, its effectiveness appears inferior to alternative chemotherapies or targeted therapies.

Chemotherapy-induced high expression of IL23A enhances efficacy of anti-PD-1 therapy in TNBC by co-activating the PI3K-AKT signaling pathway of CTLs

Treatment of advanced triple-negative breast cancer (TNBC) is a great challenge in clinical practice. The immune checkpoints are a category of immunosuppressive molecules that cancer could hijack and impede anti-tumor immunity. Targeting immune checkpoints, such as anti-programmed cell death 1 (PD-1) therapy, is a promising therapeutic strategy in TNBC. The efficacy and safety of PD-1 monoclonal antibody (mAb) with chemotherapy have been validated in TNBC patients. However, the precise mechanisms underlying the synergistic effect of chemotherapy and anti-PD-1 therapy have not been elucidated, causing the TNBC patients that might benefit from this combination regimen not to be well selected. In the present work, we found that IL-23, an immunological cytokine, is significantly upregulated after chemotherapy in TNBC cells and plays a vital role in enhancing the anti-tumor immune response of cytotoxic T cells (CTLs), especially in combination with PD-1 mAb. In addition, the combination of IL-23 and PD-1 mAb could synergistically inhibit the expression of Phosphoinositide-3-Kinase Regulatory Subunit 1 (PIK3R1), which is a regulatory subunit of PI3K and inhibit p110 activity, and promote phosphorylation of AKT in TNBC-specific CTLs. Our findings might provide a molecular marker that could be used to predict the effects of combination chemotherapy therapy and PD-1 mAb in TNBC.

Abemaciclib plus fulvestrant vs fulvestrant alone for HR+, HER2- advanced breast cancer following progression on a prior CDK4/6 inhibitor plus endocrine therapy: Primary outcome of the phase 3 postMONARCH trial.

LBA1001 Background: The combination of CDK4/6 inhibitors (CDK4/6i) + endocrine therapy (ET) is the standard first line treatment for HR+, HER2- advanced breast cancer (ABC). While disease progression occurs in nearly all patients (pts) with ABC, the optimal treatment for pts who experience progression on a CDK4/6i + ET remains uncertain. Real-world evidence suggests that use of abemaciclib after disease progression on a prior CDK4/6i prolongs progression-free survival (PFS) in ABC; however, Phase 2 trials with other CDK4/6i have generated mixed results. Here we present the primary outcome analysis for the Phase 3 postMONARCH trial (NCT05169567) of fulvestrant + abemaciclib or placebo in pts with HR+, HER2- ABC following disease progression on prior CDK4/6i + ET. Methods: postMONARCH was a global, double-blind, placebo-controlled study with pts randomized 1:1 to abemaciclib + fulvestrant or placebo + fulvestrant. Eligible pts had disease progression on a CDK4/6i + AI as initial therapy for ABC or relapse on/after a CDK4/6i + ET as adjuvant therapy for early breast cancer. No other prior treatment for ABC was permitted. Primary endpoint was investigator-assessed PFS; secondary endpoints included PFS by blinded independent central review (BICR), overall survival (OS), objective response rate (ORR), and safety. Assuming a hazard ratio (HR) of 0.7, the study had ~80% power to detect superiority for abemaciclib, with a cumulative 2-sided type I error of 0.05. Kaplan-Meier method was used to estimate PFS curves and treatment effect was estimated using a stratified Cox proportional hazard model. Results: A total of 368 pts were randomized to abemaciclib + fulvestrant (n = 182) or placebo + fulvestrant (n= 186). Most pts (99%) enrolled directly after CDK4/6i + ET as initial therapy for ABC. Prior CDK4/6i was 59% palbociclib, 33% ribociclib, and 8% abemaciclib. At interim analysis, the study reached the pre-specified criteria for significantly improved investigator-assessed PFS with abemaciclib + fulvestrant compared to placebo + fulvestrant (169 events, HR = 0.66; 95% CI 0.48 – 0.91; p = 0.01). At primary analysis (258 events), the HR was 0.73 (95% CI 0.57 – 0.95), with PFS rates at 6 months of 50% vs 37% for the abemaciclib and placebo arms, respectively. Consistent effect was seen across major clinical and genomic subgroups, including pts with baseline ESR1 or PIK3CA mutations. ORR was improved with abemaciclib compared to placebo (17% vs 7%, respectively, in pts with measurable disease). PFS according to BICR was also improved with HR = 0.55 (95% CI 0.39 - 0.77). OS remains immature (20.9% event rate). Safety was consistent with the known profile of abemaciclib. Conclusions: Abemaciclib + fulvestrant demonstrated statistically significant PFS improvement in pts with ABC progression on prior CDK4/6i-containing therapy. Clinical trial information: NCT05169567 .

Palbociclib in adults aged 70 years and older with advanced breast cancer: A phase 2 multicenter trial (Alliance A171601)

IntroductionPalbociclib is a widely used treatment for advanced breast cancer in older adults. However, the existing evidence regarding its safety and tolerability in this age group is inconsistent and limited to retrospective subgroup or pooled analyses. Materials and MethodsWe conducted a prospective single-arm multicenter phase 2 study to evaluate the safety and tolerability of palbociclib in participants aged 70 years or older with advanced hormone receptor-positive breast cancer. Participants were given palbociclib in combination with their physician's choice of endocrine therapy (letrozole or fulvestrant). The primary endpoint was the incidence of grade 3+ adverse events (AEs) by six months. Secondary endpoints included AE-related dose delays, dose reductions, early discontinuations, and hospitalizations. Additionally, we compared these endpoints by age groups (70–74 and ≥ 75 years). ResultsOf the 90 participants (median age 74 years [70–87]) enrolled, 75.6% (95% confidence interval [CI], 65.4–84.0) had grade 3+ AEs by six months. The most frequent grade 3+ AEs were neutropenia (61%), fatigue (4%), and nausea (3%). Febrile neutropenia was uncommon (1.1%). Due to AEs, 36% had dose delays, 34% had dose reductions, 10% had early discontinuations, and 10% had hospitalizations. Compared to those aged 70–74 years, participants aged ≥75 years had higher rates of early discontinuations (5.9% vs 15.9%, a difference of 9.5% [95% CI 3.5%–22.5%]). DiscussionPalbociclib has an overall favorable safety profile in adults aged ≥70 with advanced breast cancer. However, adults ≥75 years had a trend toward higher rates of AE-related early discontinuations compared to those 70–74 years. Further research is needed to evaluate tolerability and improve the delivery of palbociclib in older adults.ClinicalTrials.gov:NCT03633331

Tailoring advanced breast cancer treatment after cyclin-dependent kinase 4/6 inhibitors progression - real-world data analysis.

Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) represent the gold standard of the hormone receptor positive human epidermal growth factor receptor 2 (HER-2) negative advanced breast cancer. However, optimal treatment after disease progression is a matter of debate. We aimed to assess predictive and prognostic factors associated with the treatment outcome following CDK4/6i progression. We retrospectively analyzed patients who progressed on CDK4/6i treatment between 2018 and 2024. Treatment based on molecular findings (PIK3CA mutation), genetic findings (BRCA1/2 germline mutation), or adapted to the change in the tumor phenotype in rebiopsy (anti-HER2 therapy in the transformation to HER-2-positive disease) was grouped into tailored treatment and compared to the endocrine-based therapy and chemotherapy alone. Five hundred twelve patients were treated with CDK4/6i. Two hundred patients with disease progression were enrolled in the study. Duration of response to CDK4/6i was not predictive of the response to subsequent treatment, whereas the progression in the central nervous system was the worst prognostic factor. Thirty patients were ineligible for subsequent treatment. Survival after CDK4/6i progression was significantly longer in patients eligible for tailored treatment. The median PFS in patients with tailored treatment (n=19) was 13.5 months vs. 4.9 months in patients with non-tailored therapy (n=151; p=0.045). 12-month PFS was 54.1% with tailored treatment [95% CI 24.1-76.7%] compared to 18.5% with non-tailored therapy [95% CI 11.6-26.6%]. The median OS for patients treated with a tailored approach was not reached compared to 11.5 months with non-tailored treatment (p=0.016). The 24-month OS for patients treated with a tailored approach was 80.2% [95% CI 40.3-94.8%] compared to 21.1% [95% CI 12.2-31.7%] for patients with non-tailored treatment. Tailoring of subsequent treatment strategy seems to be essential for achieving long-term benefit. Further studies are required, as the prognosis after CDK4/6i progression remains dismal, especially in cases affecting the central nervous system.

Surface-Available HER2 Levels Alone Are Not Indicative of Cell Response to HER2-Targeted Antibody-Drug Conjugate Therapies.

HER2-targeting therapies have advanced breast cancer treatment over the past decade. Clinically, eligibility for HER2 therapies is determined by assessing HER2 levels on tumor cell surfaces through immunohistochemistry or by gene regulation through fluorescence in situ hybridization. HER2 therapies are not always effective in patients with elevated levels of HER2, questioning whether the amount of HER2 is sufficiently predictive of patient outcomes. Additionally, the HER2-targeting antibody-drug conjugate (ADC) Enhertu® was recently approved for metastasized HER2-low cancers, confirming the benefits of HER2 treatment for patients with low HER2 levels. To evaluate the correlation between HER2 levels and treatment efficacy, we quantified HER2 on eight cell lines using flow cytometry while simultaneously determining the toxicity of two HER2-targeting ADCs. Both HER2-high cell lines and HER2-low cell lines had significant toxicity responses to ADCs. We quantified HER2 internalization and found no correlation between HER2 levels and the percentage of internalization. We found a useful metric suggesting that a minimum number of HER2 receptors trafficked to lysosomes is sufficient to provide effective treatment. Our results indicate that the current standards of determining eligibility for HER2 therapy could limit patients' access to effective treatment. In conclusion, HER2 levels are not wholly adequate to determine the response to ADC treatment.

Real-world analysis of inetetamab combined with pyrotinib plus chemotherapy for the treatment of HER2-positive advanced breast cancer: A multi-center retrospective study.

e13012 Background: Inetetamab combined with tyrosine kinase inhibitors exhibited stronger antitumor effects than inetetamab alone. At present, there was few studies on the efficacy and safety of inetetamab combined with pyrotinib in the treatment of advanced breast cancer (ABC) patients. The study aims to investigate the efficacy and safety of inetetamab combined with pyrotinib plus chemotherapy for HER2-positive ABC patients. Methods: We retrospectively investigated the medical records of eligible women who aged 18 years or older with pathologically confirmed HER2-positive recurrent or metastatic invasive breast cancer, and received at least two cycles of inetetamab combined with pyrotinib plus chemotherapy treatment regimens in multicenters in China between July 2020 and December 2022. The primary endpoint was progression-free survival (PFS) estimated by the Kaplan-Meier method. The secondary endpoints were the objective response rate (ORR), disease control rate (DCR), and safety. Cox regression model was used to identify predictive factors for PFS. Results: A total of 99 patients were included. Overall patient's median PFS was 12.3 (95% CI: 10.9-13.6) months. Of 99 evaluable patients, 53 (53.5%) patients achieved objective response, including 9 (9.1%) complete response and 44 (44.4%) partial response. The remaining 45 patients achieved stable disease as the best response, thus, the DCR was 99.0%. Patients who received Inetetamab combined with pyrotinib plus chemotherapy as first-line treatment (15.0 months [95% CI: 13.6-15.8]) provided longer median PFS than that as second-line treatment (10.3 months [95% CI:9.6-10.9], p&lt;0.001). Furtherly, the Cox multivariate regression analysis indicated that patients who received inetetamab combined with pyrotinib plus albumin-bound paclitaxel for first-line treatment achieved longer median PFS. Grade 1-2 diarrhea (59.6%), vomiting (29.3%) and nausea (28.3%), hand-foot syndrome (23.2%) were the top four most common adverse events (AEs). The most common grade ≥3 AEs were leukopenia (19.2%), diarrhea (18.2%), myelosuppression (7.1%) and neutromenia (4.0%). Conclusions: The first-line treatment of inetetamab combined with pyrotinib plus chemotherapy was an effective and safe treatment for HER2-positive ABC patients. Inetetamab combined with pyrotinib plus albumin-bound paclitaxel might be the most effective combination therapies. All AEs were controllable and tolerable.

Efficacy and safety of eribulin-based chemotherapy in patients with advanced breast cancer: A single-centre retrospective study.

e13121 Background: Eribulin, a nontaxane microtubule dynamics inhibitor, which was approved for the third-line treatment of advanced breast cancer (ABC) in China in 2019. This retrospective study aimed to assess efficacy and safety of Eribulin-based chemotherapy in ABC patients, especially for patients exhibiting HER2-0 and HER2-low status (immunohistochemistry [IHC] 1+ or IHC 2+with a negative in situ hybridization assay). Methods: This single-center retrospective study planned to include 126 ABC patients from January 2020 to December 2023. Enrolled participants received Eribulin either as monotherapy or in combination with other regiments such as anti-angiogenic therapy, PD-1 inhibitor, or alternative chemotherapy in clinical practice. The primary outcomes included progression-free survival (PFS) and safety assessments. Results: A total of 84 patients with ABC received Eribulin were enrolled. Patients' baselines were summarized as follows: The median age was 53.3 years (range 30.0–86.0 years). 53 (63.1%) patients were HER2-low while 40 (47.6%) patients were hormone receptor (HR) positive. 63.1% patients have received at least one line chemotherapy before the use of Eribulin. According to the K-M survival analysis, the median PFS was 6.0 (range 3.2-11.3) months for all patients. The median PFS was longer for patients received aromatase inhibitors (AI) for over 6 months than patients with AI naive (median 10.1 vs 6.6 months; p=0.192) in HR positive patients. Patients who received CDK4/6 therapy had longer PFS than patients (median 10.7 vs 6.6 months; p=0.38). There was a trend toward prolonged PFS in the HER2-0 group compared with HER2-low group (median 10.13 vs 6.03 months; p=0.154), although there was no significant difference. A nonsignificant improvement of PFS was observed in HR-/HER2-0 patients, compare with HR-/HER2-low patients (median 16.4 vs 4.7mo; p=0.21). Meanwhile the median PFS of HER2-0 and HER2-Low was similar in HR positive patients. The objective response rate was 35.5% in HER2-0 group and 30.2% in HER2-low group. In multivariate cox regression, Eribulin as first line treatment (HR, 4.028; 95% CI, 1.131-14.337) and HER2-0 (HR, 2.903; 95% CI, 1.257-6.702) showed prognostic values regarding PFS. Common grade 3 or 4 adverse events that were reported in more than 10% were neutropenia (41.6%) and leukopenia (26.2%). No treatment-related deaths were reported. Conclusions: This single-center study demonstrated encouraging efficacy and safety in the ABC patients treated with Eribulin. Significant PFS benefit was associated with Eribulin treatment in patients with HER2-0 compared with HER2-low. This study still needs longer follow-up to evaluate its efficacy more comprehensively.

A genetically engineered epothilone analog as a novel oral microtubule inhibitor: A clinical study of utidelone capsule for advanced breast cancer.

e13115 Background: Utidelone, a genetically engineered epothilone analog, is a potential best-in-class novel microtubule stabilizing agent. Utidelone injection was approved for advanced breast cancer in China in 2021. Utidelone is not susceptible to P-glycoprotein, leading to better oral bioavailability and successful development of an oral formulation-Utidelone Capsule (UTD2). As of now, there has been no oral microtubule stabilizing agent approved in China and the United States. UTD2 may benefit patients in various aspects including effectiveness, safety, better compliance, reduced medical cost, and facilitation of combination therapy, especially with other oral anti-cancer drugs. This is the first clinical study in China to investigate the efficacy and safety of UTD2 monotherapy for treatment of advanced breast cancer. Methods: This is an ongoing open-label, multi-center study (NCT05700084) consisting of three parts: dose escalation, bioavailability and food effect, and in combination with capecitabine for treatment of metastatic breast cancer. Here we report the preliminary results from single center for part I with determination of DLT and MTD as the primary objective, and efficacy, PK profile and safety in patients with pretreated metastatic breast cancer as the secondary objectives. Eligible patients are aged 18-70 years with confirmed advanced breast cancer refractory to prior standard therapies, and have an ECOG PS of 0-1, life expectancy ≥12weeks. Patients are treated with UTD2 monotherapy, at starting dose of 50 mg/m2/d-5day for two patients, with planned escalation (3+3) to 75 mg/m2/d-5day and 75 mg/m2/d-7day, then to 85 mg/m2/d-7day or down to 70 mg/m2/d-7day in a 21-day cycle. Results: As of 25th January 2024, 5 advanced breast cancer patients were enrolled, who had received prior treatment in advanced settings. Dose escalation is ongoing, and 75mg/m2/d-7day cohort is under evaluation. Four patients were evaluated for efficacy with an outcome of 2 PR (each for 50 and 75mg/m2/d-5day dose) and 2 SD (75mg/m2/d-5day dose) with treatment durations of 2 to 8 cycles. Most treatment-emergent adverse events (TEAEs) were Grade 1/2, manageable, and included peripheral sensory neuropathy (PN), dizziness and loss of appetite. There were two patients encountered Grade 3 TEAEs including one with PN and one with diarrhea/insomnia, that recovered through dose reduction or supportive treatment. No grade 4/5 adverse events and no treatment discontinuations due to AE were reported. There have been no DLTs and the MTD is not yet reached. Conclusions: These preliminary results suggested promising efficacy with a manageable safety profile of UTD2 in pretreated metastatic breast cancer patients. This study is still actively enrolling; further data will be provided at the time of presentation. Clinical trial information: NCT05700084 .