Treatment Of Metastatic Breast Cancer Research Articles

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

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.

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.

Antibody-drug conjugates in metastatic breast cancer: sequencing, combinations and resistances.

Significant advancements have been made in treating metastatic breast cancer (MBC) with antibody drug conjugates (ADCs). However, due to the development of resistance, patients experience disease progression. The aim of this review is to summarize current evidence on ADCs sequencing strategies and combination approaches in the treatment of MBC. Concerning HER2 positive MBC, current evidence on the optimal ADC-sequencing is primarily about T-DXd, which demonstrated therapeutic value when used post-T-DM1. Conversely, data are limited about the reverse sequence. Similarly, in HER2-negative MBC, recent studies evaluated the sequential use of Sacituzumab Govitecan and T-DXd, which was associated with poor responses. Retrospective analyses have not demonstrated an optimal sequencing strategy for ADCs, and it is still very unclear whether switching the payload or targeting a different antigen may represent the best approach. Combinations may better overcome ADC resistance: interesting data associating immunotherapy or tyrosine kinase inhibitors to ADCs appear promising, albeit data are still immature. In MBC, ADCs have expanded treatment options but their sequential use requires further study. Evidence suggests that sequencing ADCs with similar payloads is ineffective, though current data are inconclusive. More research is needed to optimize treatment strategies, including potential combination therapies.

Combination Chemotherapy for Metastatic Hepatic Carcinoma and the Relation of Immune Status to the Response

Metastatic carcinoma presents a significant challenge in cancer treatment due to its aggressive nature and propensity for resistance to traditional therapeutic approaches. This systematic research paper delves into the development and evaluation of a novel combination chemotherapy regimen involving the use of 5-fluorouracil, cyclophosphamide &amp; mitomycin C, and PHA skin test in the treatment of metastatic carcinoma, lymphomas, and breast cancer. The study aims to investigate the efficacy and safety profile of this combined chemotherapeutic approach, utilizing scientific methodology and analysis to assess its potential as a promising treatment option for patients with advanced cancer.

Patient-reported convenience and effectiveness of telehealth for breast cancer management.

Before the coronavirus disease 2019 (COVID-19) pandemic, telehealth was rarely used for breast cancer management at tertiary care centers. We sought to examine patient satisfaction, experiences, preferences, and perceived effectiveness and technical quality of telehealth visits in follow-up patients receiving routine outpatient care in the breast medical oncology practice at The University of Texas MD Anderson Cancer Center. We administered a survey to 60 follow-up patients for a duration of 9 months (January 5, 2021 to October 27, 2021) who had at least one telehealth consultation during the COVID-19 pandemic, from April 10, 2020 to October 21, 2021. Descriptive statistics were then generated for each question, each domain, and overall survey scores. Subgroup comparisons within patient populations were done using the chi-square or t-test when appropriate. Among the 60 participants, 49 (82%) were undergoing standard follow-up during active treatment for either early-stage or metastatic breast cancer. Telehealth and in-person office visits were considered equivalent in terms of quality of communication by 43 participants (72%). Most participants (n = 49, 82%) felt equally cared for during telehealth and in-person visits, and 40 participants (67%) reported feeling connected to their healthcare professional during both telehealth and in-person visits. In addition, 28 participants (47%) felt that the duration of telehealth visits was similar to in-person visits, 46 (77%) found both telehealth and in-person visits equally comfortable for discussing sensitive topics, 39 (65%) considered telehealth visits convenient, and 42 (70%) perceived the overall quality of care for telehealth to be similar to that of in-person visits. Participants expressed high satisfaction with telehealth appointments, with 42 (70%) rating their experience as very satisfying. Most participants (n = 44, 73%) expressed a strong likelihood of participating in telehealth appointments for breast cancer follow-up care in the future. Our results indicate that telehealth can serve as an effective and satisfactory approach for delivering healthcare services to patients with breast cancer requiring follow-up care. The positive experiences and willingness to continue using telehealth indicate its potential for improving access to care and patient outcomes.

Concurrent use of Radiotherapy and Ribociclib: Preliminary Results and Review of the Literature.

In the recent MONALEESA-2, MONALEESA-3, and MONALEESA-7 clinical trials, the addition of ribociclib, a CDK4/6 inhibitor, to standard endocrine therapy significantly improved progression-free survival (PFS) compared with hormone therapy alone in the treatment of locally advanced or metastatic estrogen receptor-positive (ER) and HER2-negative breast cancer. However, its toxicity raises concerns when administered concomitantly with radiotherapy, leading most radiotherapists and medical oncologists to prefer to discontinue Ribociclib during radiotherapy (RT). Although there are insufficient published data on this combination, our preliminary experience with the first 2 patients treated at Institut Curie suggests promising results when using Ribociclib with Letrozole or Fulvestrant concurrently with palliative radiotherapy in the treatment of metastatic breast cancer. Our study aimed to evaluate the safety of combining Ribociclib with palliative radiotherapy in patients with metastatic breast cancer, providing crucial insights for clinical decision-making. A retrospective analysis was conducted on patients treated for hormone receptor-positive metastatic breast cancer with Ribociclib and concurrent radiotherapy at the Institut Curie (Paris, France) between September 2023 and April 2024. Among 38 patients who received Ribociclib and underwent irradiation, 36 temporarily suspended Ribociclib during radiotherapy, while 2 continued Ribociclib concurrently and were included in the analysis. Palliative radiotherapy was administered using volumetric modulated arc therapy, delivering 20Gy in 5 fractions to bone metastatic sites. Ribociclib was given at 600mg/day with hormonotherapy. Follow-up was conducted from the last day of RT until the last medical consultation. Toxicities were graded using CTCAE V5.0. Two patients received Ribociclib concomitantly with radiotherapy, experiencing pain relief without interruptions in RT. However, Ribociclib treatment was halted in both cases due to grade 3 neutropenia and grade 1 QTc interval prolongation, respectively. One patient had a dose reduction to 400mg due to neutropenia, with favorable outcomes observed. Both patients continued Ribociclib treatment, with one achieving complete remission and the other partial remission of bone disease. No late toxicities were observed. Despite the need for further investigation, our results suggest safety consistent with pivotal trials, advocating for a prospective cooperative data collection initiative to explore this combined strategy further, potentially revolutionizing metastatic breast cancer management.

Revolutionizing triple-negative metastatic breast cancer treatment: sacituzumab Govitecan's role in advancing chemotherapy.

This review aims to discuss the role and efficacy of Sacituzumab Govitecan in the management of breast cancer. Breast cancer is the most prevalent type of cancer among women worldwide. This comprehensive review delves into the advancements brought about by Sacituzumab Govitecan in the treatment of metastatic triple-negative breast cancer (TNBC). With a focus on its mode of action, efficacious role, clinical trials, and comparative advantages over conventional chemotherapy, the review highlights the therapy's precision in targeting cancer cells through monoclonal antibodies. Sacituzumab Govitecan's ability to deliver a chemotherapeutic payload specifically to cancer cells with the Trop-2 receptor sets it apart from traditional chemotherapy, minimizing collateral damage and reducing severe side effects. The impact of Sacituzumab Govitecan on improving progression-free survival, tumor response rates, and, significantly, the quality of life for patients is discussed. This article also sheds light on ongoing trials, FDA recognition, and the therapy's potential to transform breast cancer treatment. In conclusion, Sacituzumab Govitecan shows potential as an innovative therapeutic option for breast cancer, particularly in metastatic breast cancer and triple-negative breast cancer, but it warrants additional research.

CURRENT DRUG THERAPY OPTIONS FOR DISSEMINATED HER2-POSITIVE BREAST CANCER AT THE KAZAKH SCIENTIFIC RESEARCH INSTITUTE OF ONCOLOGY AND RADIOLOGY: A CLINICAL CASE

Relevance: Distant outcomes of treatment for Her2neu-positive metastatic breast cancer are improving due to access to innovative drug therapies. The study aimed to demonstrate the initial experience of treating a patient with progressive disseminated hormone receptor-positive breast cancer expressing HER2 (3+) and nearly exhausted options for anti-tumor drug therapy using trastuzumab deruxtecan. Methods: The paper describes a clinical case of a female patient born in 1977 who was diagnosed with Stage IV breast cancer (T1N1M1), invasive ductal carcinoma, and treated at the Kazakh Institute of Oncology and Radiology (Almaty, Kazakhstan). Immunohistochemical luminal subtype “B” with Her2neu (3+) expression. Metastatic involvement of skeletal bones with pain syndrome, lungs, liver, axillary, parasternal, and para-mediastinal lymph nodes. Since June 2023, monoclonal antibody conjugate trastuzumab deruxtecan therapy was initiated. The efficacy of fifth-line therapy was assessed using RECIST 1.1 before and during treatment. According to RECIST 1.1., target lesions included a conglomerate of hyperplastic axillary lymph nodes on the right, measuring 1.6 cm, parasternal lymph node 1.6 cm, a lesion in the parenchyma of the lower lobe of the left lung 1.3 cm, lesions (n=2) in the parenchyma of segment 2 of the left liver lobe 1.8 cm and 3.6 cm. Non-target lesion: hyperplastic para-mediastinal lymph nodes SLD 9.9 cm. Results: Pain syndrome was completely relieved after treatment. According to RECIST 1.1. in April 2024, after 11 courses of therapy, target lesions showed size reduction: conglomerate of hyperplastic axillary lymph nodes on the right decreased to 1.0 cm, lesion in the parenchyma of the lower lobe of the left lung increased to 2.7 cm, parasternal lymph node was not visualized, lesions (n=2) in the parenchyma of segment 2 of the left liver lobe measured 1.6 cm and 2.7 cm. Non-target lesion: hyperplastic para-mediastinal lymph nodes were not visualized. Conclusion: According to the clinical study data (DESTINY-Breast02), applying antibody-drug conjugate (ADC) demonstrates better objective response and progression-free survival time in patients previously treated with trastuzumab and taxanes.

A Lipophilic Salt Form to Enhance the Lipid Solubility and Certain Biopharmaceutical Properties of Lapatinib.

Lapatinib (LTP) commercially available as lapatinib ditosylate (LTP-DTS) salt is the only drug approved for the treatment of HER-positive metastatic breast cancer. A low and pH-dependent solubility results in poor and variable oral bioavailability, thus driving significant interest in molecular modification and formulation strategies of the drug. Furthermore, due to very high crystallinity, LTP and LTP-DTS have low solubility in lipid excipients, making it difficult to be delivered by lipid-based carrier systems. Thus, the present work reports a new salt form of LTP with a docusate counterion to enhance the pharmaceutical properties of the drug (LTP-DOC). NMR spectra showed a downfield shift of the methylene singlet proton from 3.83 and 4.41 ppm, indicating a lowering of electron density on the adjacent nitrogen atom and confirming the formation of amine-sulfonyl salt through the specified basic nitrogen center located adjacent to the furan ring. PXRD diffractograms of LTP-DOC indicated a reduced crystallinity of the prepared salt. The dissolution, equilibrium solubility, lipid excipient solubility, partitioning coefficient, distribution coefficient, tabletability, and in vitro cytotoxicity of the lipophilic salt of LTP were investigated. The equilibrium solubility data showed that LTP-DOC possesses a pH-independent solubility profile in the pH range of 3.5 to 7.4 with a 3.14 times higher permeability coefficient than commercial ditosylate salt. Furthermore, the prepared LTP-DOC salts showed twice higher log P than the free base and 8 times higher than LTP-DTS. The prepared LTP-DOC was found to have 4- to 9-fold higher solubility in lipid excipients like Capmul MCM C8 and Maisine CC compared to the ditosylate salt. The LTP-DOC salt was tabletable and showed approximately 1.2 times lower dissolution than commercial ditosylate salt, indicating extended-release behavior. A cytotoxicity study of LTP-DOC salt showed an approximately 2.5 times lower IC50 value than the LTP-free base and 1.7 times lower than commercial ditosylate salt with an approximately 3 times higher selectivity index. The investigations strongly indicate a high translational potential of the prepared salt form in maintaining solubility-lipophilicity interplay, enhancing the drug's bioavailability, and developing lipidic formulations.

Preclinical studies of BB-1701, a HER2-targeting eribulin-containing ADC with potent bystander effect and ICD activity.

Several HER2-targeting antibody-drug conjugates (ADC) have gained market approval for the treatment of HER2-expressing metastasis. Promising responses have been reported with the new generation of ADCs in patients who do not respond well to other HER2-targeting therapeutics. However, these ADCs still face challenges of resistance and/or severe adverse effects associated with their particular payload toxins. Eribulin, a therapeutic agent for the treatment of metastatic breast cancer and liposarcoma, is a new choice of ADC payload with a distinct mechanism of action and safety profile. We've generated a novel HER2-tageting eribulin-containing ADC, BB-1701. The potency of BB-1701 was tested in vitro and in vivo against cancer cells where HER2-expressing levels vary in a large range. Bystander killing effect and toxin-induced immunogenic cell death (ICD) of BB-1701 were also tested. In comparison with HER2-targeting ADCs with DM1 and Dxd payload, eribulin-containing ADC demonstrated higher in vitro cytotoxicity in HER2-low cancer cell lines. BB-1701 also effectively suppressed tumors in models resistant to DM1 or Dxd containing ADCs. Mode of action studies showed that BB-1701 had a significant bystander effect on HER2-null cells adjacent to HER2-high cells. In addition, BB-1701 treatment induced ICD. Repeated doses of BB-1701 in nonhuman primates showed favorable pharmacokinetics and safety profiles at the intended clinical dosage, route of administration, and schedule. The preclinical data support the test of BB-1701 in patients with various HER2-expressing cancers, including those resistant to other HER2-targeting ADCs. A phase I clinical trial of BB-1701 (NCT04257110) in patients is currently underway.

Real-world use patterns, effectiveness, and tolerability of sacituzumab govitecan for second-line and later-line treatment of metastatic triple-negative breast cancer in the United States.

Patients with metastatic triple-negative breast cancer (mTNBC) have poor prognosis and limited treatment options. Sacituzumab govitecan (SG), a Trop-2-directed antibody-drug conjugate, is approved for patients with mTNBC who have received ≥ 2 systemic therapies (≥ 1 in the metastatic setting) based on the ASCENT study (NCT02574455). The current study describes real-world SG use and outcomes in patients with mTNBC in the United States. This retrospective, observational study included adult patients with mTNBC from the ConcertAI Patient360™ database who received SG in the second line (2L) and later from April 2020 to May 2022. SG use patterns, effectiveness, and tolerability are described. This analysis included 230 patients (median age 60years, 26% Black, 17% with ECOG performance status ≥ 2, 66% in community settings; median of 2 prior lines of treatment in the metastatic setting); median follow-up was 7.2months. Median (95% CI) real-world overall survival was 10.0 (8.3-11.1) months for all patients and 13.9 (9.8-not estimable) months in the 2L subgroup (n = 77). Granulocyte-colony stimulating factor (G-CSF) was administered concomitantly with SG in 134 (58%) patients; 35 (15%) received G-CSF for the first time. Median (IQR) time from SG start to G-CSF use was 8.5 (8.0-29.0) days. Seventeen (7%) patients discontinued SG due to toxicity. Using a real-world, ethnically diverse population of patients with mTNBC presenting with poor prognosis, these data reinforced the findings from ASCENT. In routine clinical practice, SG is an effective treatment in the 2L setting, consistent with treatment guidelines.

Eribulin in breast cancer: Current insights and therapeutic perspectives.

Eribulin is a non-taxane synthetic analogue approved in many countries as third-line treatment for the treatment of patients with metastatic breast cancer. In addition to its mitotic property, eribulin has non-mitotic properties including but not limited to, its ability to induce phenotypic reversal of epithelial to mesenchymal transition, vascular remodelling, reduction in immunosuppressive tumour microenvironment. Since approval, there has been a surge in studies investigating the application of eribulin as an earlier-line treatment and also in combination with other agents such as immunotherapy and targeted therapy across all breast cancer sub-types, including hormone receptor positive, HER2 positive and triple negative breast cancer, many demonstrating promising activity. This review will focus on the application of eribulin in the treatment of metastatic breast cancer across all subtypes including its role as an earlier-line agent, its toxicity profile, and potential future directions.