Treatment Of Metastatic Breast Cancer Research Articles

Docetaxel-tethered di-Carboxylic Acid Derivatised Fullerenes: A Promising Drug Delivery Approach for Breast Cancer.

Docetaxel (DTX) has become widely accepted as a first-line treatment for metastatic breast cancer; however, the frequent development of resistance provides challenges in treating the disease.C60 fullerene introduces a unique molecular form of carbon, exhibiting attractive chemical and physical properties. Our study aimed to develop dicarboxylic acid-derivatized C60 fullerenes as a novel DTX delivery carrier. This study investigated the potential of water-soluble fullerenes to deliver the anti-cancer drug DTX through a hydrophilic linker. The synthesis was carried out using the Prato reaction. The spectroscopic analysis confirmed the successful conjugation of DTX molecules over fullerenes. The particle size of nanoconjugate was reported to be 122.13 ± 1.63nm with a conjugation efficiency of 76.7 ± 0.14%. The designed conjugate offers pH-dependent release with significantly less plasma pH, ensuring maximum release at the target site. In-vitro cell viability studies demonstrated the enhanced cytotoxic nature of the developed nanoconjugate compared to DTX. These synthesized nanoscaffolds were highly compatible with erythrocytes, indicating the safer intravenous route administration. Pharmacokinetic studies confirmed the higher bioavailability (~ 6 times) and decreased drug clearance from the system vis-à-vis plain drug. The histological studies reveal that nanoconjugate-treated tumour cells exhibit similar morphology to normal cells. Therefore, it was concluded that this developed formulation would be a valuable option for clinical use.

P89-1 Comparative effectiveness of T-DM1 and T-DXd in the treatment of metastatic breast cancer: a systematic review of RCTs

P89-1 Comparative effectiveness of T-DM1 and T-DXd in the treatment of metastatic breast cancer: a systematic review of RCTs

MO53-4 Sacituzumab Govitecan-Hziy as treatment in metastatic breast cancer: a systematic review and meta-analysis of RCTs

MO53-4 Sacituzumab Govitecan-Hziy as treatment in metastatic breast cancer: a systematic review and meta-analysis of RCTs

Adaptive learning to address gaps in metastatic breast cancer treatment with CDK 4/6 inhibitors.

92 Background: To address identified gaps in knowledge and confidence of US-based healthcare professionals (HCPs) when using cyclin-dependent kinase 4/6 inhibitors (CDK 4/6i) to treat metastatic breast cancer (mBC), an adaptive learning program (ALP) was deployed to review guideline recommendations and evidence from randomized clinical trials (RCTs) and real-world data (RWD). Methods: The ALP consisted of reading materials (guideline excerpts, RCTs, RWD, cases) with a virtual tutor that taught. The ALP continued to review necessary content until responders were both correct and confident (conscious competence). Impact on learning was interpreted as greater for learning objectives with the lowest accuracy score (% of correct responses) and higher distance to 100% conscious competency at baseline. Immediately post-ALP, satisfaction, perceived impact on knowledge, confidence and intent to change practice were assessed quantitatively and qualitatively. ANOVA compared continuous measures by profession. Results: Participants (n=261) were physicians (MD, 17%), advanced practice practitioners (APP, 20%), registered nurses (RN, 49%), pharmacists (11%), and other (3%). Mean completion time was 44 minutes and learners’ proficiency shifted +64% towards conscious competency. The learning objectives most impacted by the education are shown (Table). Learners most satisfied with the ALP (47% with 9-10 on a 10-point satisfaction scale) appreciated the challenge and reported positive impact on their knowledge and confidence, resulting in intent to change their patient-communication, clinical decisions and interprofessional collaboration when using CDK4/6i. Conclusions: This ALP initiative addressed the educational gaps of US HCPs regarding CDK4/6i in HR+/HER2- mBC by challenging participants to re-consider their knowledge and confidence until conscious competency was demonstrated. Engaged learners found the activity impactful and reported intent to change practice. Future studies should seek to address attrition challenges and assess long term impacts of such programs. Top five learning objectives with lowest-ranking accuracy, by profession. Learning Objectives (LOs) Most Impacted Initial Scores by Profession Final Score ALL MD APP RN PharmD Other Identify appropriate CDK4/6i treatment options for a premenopausal woman with newly diagnosed HR+/HER2- mBC 54 57 53 53 62 52 100 Match RWD sources with their characteristics 56 55 60 55 61 41 100 Interpret results from the landmark CDK4/6i RCTs 58 62 61 53 64 56 100 Interpret RWE related to the use of CDK4/6i in patients who are underrepresented in RCTs* 62 62 63 58 74 65 100 Identify the latest updates from CDK4/6i RCTs 62 60 63 61 62 82 100 Average accuracy score for all 24 LOs 71 72 73 69 74 64 100 *Significantly different between professions (p<0.05; one-way ANOVA).

Real-World Clinical Outcomes With Sacituzumab Govitecan in Metastatic Triple-Negative Breast Cancer.

Sacituzumab govitecan (SG) is approved for the treatment of metastatic triple-negative breast cancer (mTNBC). We report the real-world clinical effectiveness and toxicity data of SG in patients with mTNBC. A multi-institution retrospective study of patients with mTNBC treated with SG from January 2021 to May 2023 was conducted. Demographic and clinicopathologic variables were collected. Univariate and multivariate Cox regression models were used for survival analysis. A total of 115 patients were included. The median age at SG initiation was 60 years (range, 31-85). All patients were female; 73 (63.5%) were White and 31 (27.0%) were Black. The median number of previous therapies in the metastatic setting was two (range, 0-8). Sixty-one (56.0%) patients had primary refractory disease. Median relative dose intensity was 92% (range, 33%-100%). Grade 3 or higher adverse events (AEs) were seen in 50.9% of patients, which included neutropenia (35.7%), anemia (27.0%), vomiting (16.5%), fatigue (8.7%), and diarrhea (7.0%). Dose reductions and treatment discontinuation due to AEs were required in 51.3% and 13.2%, respectively. The objective response rate (ORR) was 27.8%. Median overall survival was 9.6 months (95% CI, 7.8 to 12.9) and median progression-free survival (PFS) was 4.8 months (95% CI, 3.6 to 5.9). In patients with human epidermal growth factor receptor 2 (HER2)-low mTNBC who received trastuzumab deruxtecan (T-DXd) after SG, the ORR to T-DXd was 34.8% and median PFS was 7 months (95% CI, 4.6 to 10.1). In a real-world cohort of heavily pretreated patients with mTNBC, SG retains its clinical activity. In a subgroup with HER2-low disease, T-DXd continues to demonstrate promising clinical activity after SG, supporting the use of sequential antibody-drug conjugates in this population.

Frustrations with time spent on cancer care among patients with metastatic breast or advanced ovarian cancer.

235 Background: Individuals with cancer face substantial demands on their energy and time due to the complexity of cancer care. We sought to describe frustrations with time-consuming aspects of cancer care among individuals with advanced ovarian or breast cancer. We hypothesized that frustrations would be highest for time spent on administrative tasks, particularly for those who are younger, employed, and have dependents. Methods: We analyzed baseline survey data from an ongoing prospective study of the time burdens of cancer care among individuals receiving treatment for ovarian or metastatic breast cancer at the University of Minnesota and University of Alabama-Birmingham. The survey included questions about frustrations with the time needed for cancer-related activities such as travel time, finding transportation, care coordination, receiving treatment, and paperwork (0=Not at all, 10=Extremely frustrated). We summarized the data using descriptive statistics and made comparisons across demographic and clinical characteristics using Wilcoxon rank-sum and Kruskal-Wallis tests. Results: A total of 67 participants completed the baseline survey, 37 (55.2%) with metastatic breast cancer and 30 (44.8%) with ovarian cancer. About 1/4 of participants (26.9%) were under 50 years old, 34.3% had dependents, 39.1% were employed, and 57.6% lived 30+ miles from the cancer clinic; 73.1% were non-Hispanic (NH) White and 22.4% NH Black; 4.5% reported another race/ethnicity. Over half (58.2%) agreed minimizing time spent on cancer-related activities was important to them; those employed were significantly more likely to agree (76.0% vs. 48.7%, p=0.03). Activities with the highest reported frustrations were the number of trips, time for care-related travel or paperwork, and wait time. Younger participants reported higher frustration with wait time (p=0.04) and time at the infusion center than older participants (p=0.03). Employed participants reported significant frustration with having to take time off work (p<0.0001), and those with dependents reported frustration needing to organize dependent care (p=0.01). Participants living 30+ miles from the cancer clinic reported greater frustrations with travel time (p=0.01), time needed for care coordination (p=0.01) and waiting for the provider (p=0.02). Some (10.6%) participants reported lacking reliable transportation and, among those, reported high frustration with the time needed for numerous activities, including finding transportation, paperwork, care coordination, and making appointments (all p<0.05). Conclusions: Cancer-related time demands are frustrating for many patients. Those employed, younger, with dependents, living further from the cancer clinic, and without reliable transportation experience greatest frustrations about time lost, underscoring the need to address these often unrecognized aspects of care.

Perspectives on Death and Dying by the Bereaved Designated Personal Representatives of Women Diagnosed With Metastatic Breast Cancer.

Metastatic breast cancer (MBC) is a complex disease with variability in disease subtype, length of survival, treatment selection, symptom burden, and, ultimately, end-of-life (EOL) care. Influencing factors that contribute to the complexity of this disease are socioeconomic factors, provider differences, and patient and family preferences. Because of this variability, it is challenging for health care providers to know when treatments are no longer helpful but contribute to a poor quality of end-of-life care and a poor death experience for both patients and their families. Determining the unique point, based on their own values and goals, at which patients and their family members feel that MBC treatment becomes unhelpful and unwanted, is difficult to ascertain. Of the 25 individuals who participated in the Quality of Death and Dying survey, 16 individuals participated in an interview to provide a reflection of the patient's EOL experience and its congruence with their wishes. Four major categories emerged as primary priorities essential to high quality end-of-life care, that is, resilience, communication, support, and knowledge. Without tailored and precise care, patients with MBC will continue to receive prolonged, inappropriate, and costly treatment, resulting in a potentially unacceptable poor-quality EOL and death experience.

Personalized treatment approach for HER2-positive metastatic breast cancer.

Breast cancer (BC) is a leading global concern for women, with 30% being HER2-positive cases linked to poorer outcomes. Targeted therapies like trastuzumab deruxtecan (T-DXd), trastuzumab, pertuzumab, and T-DM1 have revolutionized HER2-positive metastatic breast cancer (MBC) treatment. Although these therapies have improved MBC management and patient outcomes, resistance can develop, reducing effectiveness. Personalized strategies based on tumor characteristics offer hope for better responses and longer outcomes. This review outlines insights into MBC patients responding well to anti-HER2 treatments, even across multiple treatment regimen. Recent immunotherapy, locoregional therapy, and liquid biopsy breakthroughs are covered, suggesting ways to increase long-term responders. Personalized approaches have boosted HER2-positive MBC outcomes, and ongoing research is crucial to uncover new treatments and biomarkers, potentially elevating long-term response rates and prognoses. This may aid in providing new direction to breast cancer clinics.

Investigating the Salience of Clinical Meaningfulness and Clinically Meaningful Outcomes in Metastatic Breast Cancer Care Delivery

PURPOSE As metastatic breast cancer (mBC) treatment evolves, there is a need to understand how clinical meaningfulness, or a meaningful change in a patient's daily life, and clinically meaningful outcomes inform patient-centered care. Partnering with key stakeholders ensures patient-centered research incorporates the knowledge and expertise of advisors with lived experience. We describe a multistakeholder engagement approach to examine how people living with mBC (PLWmBC), caregivers, and health care providers interpret clinical meaningfulness and clinically meaningful outcomes and their influence on mBC treatment decision making and care. METHODS Qualitative focus groups with PLWmBC, caregivers, and health care providers were conducted and analyzed along three overarching themes: interpretations of clinical meaningfulness and clinically meaningful outcomes; treatment recommendations, preferences, and decisions; and implications for clinical practice. Patient-led and professional organizations served as research partners in study design, implementation, and interpretation of findings. RESULTS Partnerships were established with four patient-led and three professional organizations representing diverse constituencies throughout the United States. Twenty-two focus groups were conducted with 50 PLWmBC, 24 caregivers, and 41 health care providers (oncologists, n = 11; advanced practice providers, n = 13; oncology nurses, n = 17) between March and June 2023. PLWmBC and caregivers were unfamiliar with the concepts of clinical meaningfulness and clinically meaningful outcomes. Although health care providers were familiar, they did not use the terms when discussing treatment with PLWmBC. Across groups, participants emphasized the importance of meaningful outcomes beyond overall survival, including quality of life and improvement in symptoms and functioning. Participants noted that outcomes considered meaningful are individualized and dynamic. CONCLUSION This study offers insight into how partnering with patient advocacy and professional organizations can enhance research quality and aid translation of findings to clinical practice, thereby supporting patient-centered care.

Safety profile of trastuzumab originator vs biosimilars: a systematic review and meta-analysis of randomized clinical trials.

In the last decade trastuzumab biosimilars became more and more frequent. Among their uses, from several years, they have been available in Europe for the treatment of HER2-positive metastatic breast cancer, as an alternative to Herceptin®. This meta-analysis aimed to analyze the available literature with particular focus on phase 3 randomized clinical trials (RCTs) comparing adverse events between trastuzumab biosimilar and originator. A systematic review was conducted in Pubmed and Scopus to include all phase 3 RCTs related to trastuzumab in patients with HER2-positive breast cancer and published up to July 31, 2023. Of the 508 records identified, 14 articles were meta-analyzed for safety information, including serious treatment emergent adverse events, death-related adverse events, neutropenia, leukopenia, infections, increased ALT, increased AST, anti-drug antibody, and neutralizing antibody. Included patients had an early breast cancer (N=2,877) or a metastatic breast cancer (N=2,603). No significant difference in death-related adverse events was found for trastuzumab biosimilar and originator when evaluated for an early breast cancer in the neoadjuvant phase (Risk Ratio [RR], 1.30; 95% confidence interval [CI], 0.47-3.59; I2 = 0%; p = 0.57) and overall (RR, 0.43; 95%CI, 0.11-1.66; I2 = 20%; p = 0.26), and for metastatic breast cancer (RR, 0.61; 95%CI, 0.30-1.26; I2 = 0%; p = 0.85). No difference was also observed for all other safety outcomes as in accordance with clinical studies necessary for the registration and approval of a biosimilar at a European level.

The choice of optimal therapy for ER+ HER2-metastatic breast cancer (PROMETHEUS): all-Russian analysis of physicians’ preferences – updated survey results

Cyclin-dependent kinase 4/6 inhibitors (iCDK4/6) are the generally accepted standard of care for the treatment of luminal HER2-negative metastatic breast cancer (ER+HER2- mBC). Data from randomized and observational studies have proven the high effectiveness of the combination of iCDK4/6 and endocrine therapy (ET) both in the 1st and in subsequent lines. The use of new drugs in real clinical practice is determined by a number of factors, including the awareness of doctors, their personal experience and subjective preferences, as well as financial support and availability in a particular region. To assess the frequency of prescription of CDK4/6, as well as other types of treatment in the 1st‑2nd line of therapy for ER+ HER2- mBC in real clinical practice in Russia, as well as to determine the factors and preferences of doctors influencing their choice, the National Association of Oncomammologists (NAOM) conducted a survey “Prometheus” of oncology specialists. From February 15 to August 30, 2023, a web survey of healthcare professionals who treat patients with mBC was conducted on the website anketolog.ru. An invitation to survey was sent out through the NAOM database, 112 questionnaires were received and processed. Earlier, in 2020, the “Prometheus” survey was conducted on the territory of the Russian Federation for a similar purpose. In this paper, we present the results of an updated and expanded survey and evaluate changes that have occurred over the past 3 years in actual clinical practice. The results of a 2023 survey conducted in the Russian Federation on the choice of early-line therapy for ER+HER2- mBC showed that, compared with the 2020 survey, the level of “trust” in iCDK4/6 has increased among practicing physicians, and the indications for their use have expanded, including visceral metastases (and even pending visceral crisis), the indications for prescribing chemotherapy in the 1st line have narrowed. When using monoET in the 1st line, the majority of respondents prescribe iCDK4/6 in the 2nd line. Obviously, the wider use of iCDK4/6 is associated not only with the accumulation of clinical knowledge and experience in the use of drugs, but also with improved drug supply. However, the main limitations to the use of iCDK4/6 are still insufficient funding and organizational difficulties. However, it should be noted that 1/5 of the respondents do not face any restrictions and widely prescribe combination therapy.

Novel Antibody-Drug-Conjugates in Routine Clinical Practice for the Treatment of Metastatic Breast Cancer: Adherence, Efficacy and Tolerability - Real-World Data from German Breast Centers.

The third-generation antibody-drug conjugates (ADC), trastuzumab deruxtecan (T-DXd) and sacituzumab govitecan (SG), recently obtained approval for metastatic breast cancer treatment across various subtypes and therapeutic contexts. This retrospective, multicentric study evaluated real-world tolerability, feasibility and efficacy in a pre-treated, real-world cohort at three major German breast cancer centers. 125 patients treated with T-DXd or SG from November 2020 to June 2023 were included (T-DXd: 77 patients; SG: 48 patients). The median treatment duration was 6.0 months for T-DXd and 3.5 months for SG therapy, with a median follow-up duration of 10.4 months for T-DXd (95% CI: 8.4-11.6) and 11.8 months for SG (95% CI: 8.0-14.4). Severe neutropenia (CTC≥III°) occurred in 33.3% during SG therapy, with a numerical reduction observed following primary, prophylactic use of G-CSF. T-DXd-associated pneumonitis occurred in 8 out of 77 patients (10.4 %). Median progression-free survival (mPFS) was 8.6 months (95% CI: 5.8-12.4) with T-DXd (HER2+: 10.8; HER2-low: 4.7) and 4.9 months (95% CI: 2.8-6.3) with SG (TNBC 4.9; HR+/HER2-: not reached). Median overall survival (OS) was 23.8 months (95% CI: 16.1-not estimable) with T-DXd (HER2+: 27.1; HER2-low: not reached), and 12.4 months (95% CI: 8.7-not estimable) with SG therapy (TNBC: 12.4, HR+/HER2-: not reached). 95.7% of the protocol-specified, therapeutic dose was administered for T-DXd and 89.6% for SG. Overall, this indicates good feasibility, tolerability, and effectiveness of ADC therapies in the real-world setting.

395P Receptor status heterogeneity during metastatic breast cancer treatment

395P Receptor status heterogeneity during metastatic breast cancer treatment

Experience With Palbociclib in Metastatic Breast Cancer Patients Managed Under a Government Health Scheme at a Cancer Care Center in Southern India.

Introduction According to Globocan 2022, breast cancer ranks number one among the cancers worldwide. South Asian women have a higher incidence comparedto Westerners. Estrogen receptor (ER) and progesterone receptor (PR) positive tumors, termed hormonal receptor-positive tumors, account for most breast cancer presentations. In India, advanced-stage presentations are more common. In metastatic hormone receptor-positive breast cancer, hormonal therapy combined with cyclin-dependent kinase (CDK) 4/6 inhibitors is the standard treatment. Aim This study aimed to analyze the experience with generic palbociclib provided under the Government Health Scheme for metastatic hormone receptor-positive breast cancer at our institution. Methods This retrospective study was conducted on breast cancer patients admitted to a tertiary carecenter in South India. The data of ER and PR receptor-positive metastatic breast cancer patients who received palbociclib were identified and reviewed using medical records from 2023 to 2024. Results A total of 238 patients were analyzed, of which41 received palbociclib for hormone receptor-positive metastatic breast cancer. The median age was 49 (33-75), with 53.5% (22) of women above 50. Denovo stage IV presentation was observed in 21patients (51.2%), while progression to stage IV disease was noted in 11 patients (26.8%), and stages II and IIIwere noted in nine patients (22%). Invasive ductal carcinoma was the most common histology. All patients were ER-positive, and 38 (92.7%) were PR-positive. About 17 patients (41.5%) had visceral metastasis, and 12 (29.3%) had bone-only metastasis. Local recurrence was seen in six patients (14.6%), and bone with visceral metastasis was seen in another six patients (14.6%). Progression within one year of hormonal therapy initiation was observed in 50% (10) of patients. Among 21 patients with upfront metastasis, nine were treated with prior chemotherapy. All patients were given 125 mg of oral palbociclib. Fatigue was the most common side effect in 34.1% (14), followed by myalgia in 21.9% (9), low hemoglobin levels of less than 8 g/dl in 14.6% (6), and nausea and vomiting in only 9.8% (4) of patients. Conclusion Hormone therapy combined with CDK4/6 inhibitors is the backbone of treatment for metastatic hormone-positive breast cancer. However, in developing countries like India, where most patients come from rural areas, using innovator palbociclib may not be feasible for many. With the availability of generic palbociclib under the Government Health Scheme, patients of metastatic hormone receptor-positive breast cancer will receive the protocol-based treatment.

LBA19 Capivasertib (C) + paclitaxel (P) as first-line treatment of metastatic triple-negative breast cancer (mTNBC): The CAPItello-290 phase III trial

LBA19 Capivasertib (C) + paclitaxel (P) as first-line treatment of metastatic triple-negative breast cancer (mTNBC): The CAPItello-290 phase III trial

396P Evaluation of MUC1-C/CD3 biparatopic-bispecific (BPBS) T cell engager as an immunotherapeutic agent for the treatment of MUC1-expressing metastatic breast cancer (mBC)

396P Evaluation of MUC1-C/CD3 biparatopic-bispecific (BPBS) T cell engager as an immunotherapeutic agent for the treatment of MUC1-expressing metastatic breast cancer (mBC)

THE PROFILE AND CLINICAL EVIDENCE OF EFFECTIVENESS OF OLAPARIB IN TRIPLENEGATIVE BREAST CANCER: A REVIEW

Triple-negative breast cancer (TNBC) is one of the most common malignancies in women. The majority of patients with TNBC have a poor prognosis. The main objective of this study is to review the profile and clinical evidence of the effectiveness of Olaparib in treating TNBC. A literature search was conducted using multiple electronic databases, including PubMed, Google Scholar, JSTOR, and Scopus. The search was focused on articles published up to June 2024, ensuring the inclusion of the latest and relevant studies. The primary objective was to investigate the mechanism of action, toxicity profile, resistance mechanisms, and therapeutic effectiveness of olaparib in the treatment of TNBC, regardless of their prior chemotherapy treatment for metastatic breast cancer, prior platinum-based chemotherapy, or usage of cyclin-dependent kinase 4/6 inhibitors (Balmana et al., 2022). The results of this research suggest that the pharmacological efficacy and safety characteristics of this medication in TNBC patients are similar to those reported in the OlympiAD study. Furthermore, stratification of patients for this medication is possible due to the diagnostic techniques that can predict the presence of the BRCA mutation in order to optimize its efficacies. Additionally, developing and validating new biomarkers beyond BRCA mutations for patient stratification could optimize targeted therapy approaches.

OPERA-01: A randomized, open-label, phase 3 study of palazestrant (OP-1250) vs standard-of-care for patients with ER+, HER2- advanced or metastatic breast cancer after endocrine therapy and CDK4/6 inhibitors.

TPS22 Background: In estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2–) metastatic breast cancer (MBC), endocrine therapy (ET) plus a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) is the standard-of-care (SOC) treatment in the first-line setting. However, patients develop resistance, most commonly due to acquired mutations in ESR1. Efficacy of available ET post CDK4/6i treatment is limited. Therefore, a significant unmet need exists for patients with ET-CDKi-resistant ER+, HER2– MBC to improve outcomes and delay time to chemotherapy. Palazestrant is an oral small molecule complete ER antagonist (CERAN) and selective ER degrader (SERD) that binds ER and completely blocks ER-driven transcriptional activity, irrespective of ESR1 mutation status. In a phase 1/2 monotherapy study in heavily pretreated patients with ER+, HER2– advanced or MBC (NCT04505826), palazestrant showed a tolerable safety profile, favorable pharmacokinetics and encouraging antitumor efficacy in patients with and without ESR1 mutation at the recommended Phase 2 dose of 120 mg once a day (qd) (Lin et al. ESMO 2023 MO382). Methods: OPERA-01 (NCT06016738) is a multicenter, randomized, open-label, phase 3 clinical trial comparing the efficacy and safety of palazestrant as a single agent to SOC ET (fulvestrant, anastrozole, letrozole, or exemestane) in patietns with ER+, HER2– MBC that relapsed or progressed on 1-2 prior lines of ET, including a CDK4/6i. Eligible patients are adults who have a confirmed diagnosis of evaluable ER+, HER2– inoperable locally advanced or MBC and an Eastern Cooperative Oncology Group performance status of 0 or 1. Prior treatments must include 1-2 prior lines of ET, last ET duration for ≥6 months; must have received CDK4/6i with ET and have disease progression during or within 28 days of completion of each line of prior treatment for MBC. No prior chemotherapy in the metastatic setting is permitted. In the dose selection part of the study, 120 patients are randomized to 90 mg qd or 120 mg qd palazestrant or SOC monotherapy. The dose selection will be conducted when 80 patients in both palazestrant arms have had an opportunity to be on treatment for 16 weeks. Overall, 510 patients, including patients from the dose selection part, will be randomized to palazestrant or SOC ET. The primary endpoint of progression-free survival will be assessed by blinded independent central review in patients with and without ESR1 mutations in the intent-to-treat population. Secondary endpoints include overall survival, antitumor activity (objective response rate, clinical benefit rate, and duration of response), safety, patient-reported outcomes, and PK in patients with and without ESR1 mutations. The study started recruitment in November 2023. Clinical trial information: NCT06016738 .

Global Study on the Accuracy of Human Epidermal Growth Factor Receptor 2-Low Diagnosis in Breast Cancer.

Recently, a new type of antibody-drug conjugate, trastuzumab-deruxtecan (T-DXd), has been approved for the treatment of metastatic breast cancer with low level of human epidermal growth factor receptor 2 (HER2) gene expression. Thereby, eligibility relies on an accurate diagnosis of HER2-low status defined by immunohistochemistry IHC 1+/2+ with no gene amplification. To assess pathologists' accuracy and training efficacy in the diagnosis of HER2-low. Agreement rates of HER2-low scoring in breast cancer tissue were assessed between expert consensus and real-world pathologists (n = 77 from 14 countries) before and after a specific 4-hour training for HER2-low detection. Two assays were evaluated, the Ventana Pathway 4B5 CDx and the Dako HercepTest (polyclonal). Concordance of the pathologists with consensus score and efficacy of training were measured by Cohen κ, overall rater agreement, and receiver operating characteristic (ROC) curve statistics. In the Ventana 4B5 HER2-low category, baseline agreement rates were >80% but <90%. Negative percentage agreement was improved from 80.6% to 91.1% by training. In the HER2-0 category, positive percentage agreement (74.6%) was the only parameter below the 80% benchmark but was significantly improved to 89.2% after training. Training efficacy was confirmed by ROC curve analysis, which shows improvement for the identification of HER2-0 and HER2-low cases. Finally, in-depth examination of cases with discordant HER2 status disclosed specific issues of HER2-low underscoring and overscoring. The ability of pathologists to achieve acceptable diagnostic accuracy in identifying patients with HER2-low breast cancer could be enhanced by short-term training. Potential routes to improve the quality of HER2-low scoring in clinical practice have been identified.

αvβ3 Integrin and Folate-Targeted pH-Sensitive Liposomes with Dual Ligand Modification for Metastatic Breast Cancer Treatment.

The advent of pH-sensitive liposomes (pHLips) has opened new opportunities for the improved and targeted delivery of antitumor drugs as well as gene therapeutics. Comprising fusogenic dioleylphosphatidylethanolamine (DOPE) and cholesteryl hemisuccinate (CHEMS), these nanosystems harness the acidification in the tumor microenvironment and endosomes to deliver drugs effectively. pH-responsive liposomes that are internalized through endocytosis encounter mildly acidic pH in the endosomes and thereafter fuse or destabilize the endosomal membrane, leading to subsequent cargo release into the cytoplasm. The extracellular tumor matrix also presents a slightly acidic environment that can lead to the enhanced drug release and improved targeting capabilities of the nano-delivery system. Recent studies have shown that folic acid (FA) and iRGD-coated nanocarriers, including pH-sensitive liposomes, can preferentially accumulate and deliver drugs to breast tumors that overexpress folate receptors and αvβ3 and αvβ5 integrins. This study focuses on the development and characterization of 5-Fluorouracil (5-FU)-loaded FA and iRGD surface-modified pHLips (FA-iRGD-5-FU-pHLips). The novelty of this research lies in the dual targeting mechanism utilizing FA and iRGD peptides, combined with the pH-sensitive properties of the liposomes, to enhance selective targeting and uptake by cancer cells and effective drug release in the acidic tumor environment. The prepared liposomes were small, with an average diameter of 152 ± 3.27 nm, uniform, and unilamellar, demonstrating efficient 5-FU encapsulation (93.1 ± 2.58%). Despite surface functionalization, the liposomes maintained their pH sensitivity and a neutral zeta potential, which also conferred stability and reduced aggregation. Effective pH responsiveness was demonstrated by the observation of enhanced drug release at pH 5.5 compared to physiological pH 7.4. (84.47% versus 46.41% release at pH 5.5 versus pH 7.4, respectively, in 72 h). The formulations exhibited stability for six months and were stable when subjected to simulated biological settings. Blood compatibility and cytotoxicity studies on MDA-MB-231 and SK-BR3 breast cancer cell lines revealed an enhanced cytotoxicity of the liposomal formulation that was modified with FA and iRGD compared to free 5-FU and minimal hemolysis. Collectively, these findings support the potential of FA and iRGD surface-camouflaged, pH-sensitive liposomes as a promising drug delivery strategy for breast cancer treatment.