Treatment Of Metastatic Breast Cancer Research Articles

Cost-effectiveness model of trastuzumab deruxtecan as second-line treatment in HER2-positive unresectable and/or metastatic breast cancer in Finland

ObjectivesTrastuzumab deruxtecan (T-DXd) was recently recommended by the Committee for Medicinal Products for Human Use as a treatment for adult patients with unresectable or metastatic HER2-positive breast cancer, who had received a prior anti-HER2-based regimen. In our study, we evaluated the cost-effectiveness of T-DXd compared with ado-trastuzumab emtansine (T-DM1) for this indication in Finland.MethodsA three-state partitioned survival analysis model was developed with a payer’s perspective. Time to event data from the DESTINY-Breast03 (DB-03) trial were extrapolated over a lifetime horizon either directly—for progression-free survival and time to treatment discontinuation—or using an alternative approach utilizing long-term T-DM1 survival data and DB-03 data—for overall survival. Discount rates of 3% were applied for costs and effects. Inputs were sourced from the Medicinal Products Database from Kela, Helsinki University Hospital service price list, Finnish Medicines Agency assessments, clinical experts, and DB-03. Sensitivity analyses were performed to characterize and demonstrate parameter uncertainties in the model.ResultsTotal quality-adjusted life years (QALYs) and life years (LYs) gained for T-DXd compared with T-DM1 were 1.93 and 2.56, respectively. Incremental costs for T-DXd compared with T-DM1 were €106,800, resulting in an ICER of €55,360 per QALY gained and an ICER of €41,775 per LY gained. One-way sensitivity analysis showed the hazard ratio of T-DXd vs T-DM1 for OS was the most influential parameter. The probabilistic sensitivity analysis showed similar results to the base case.ConclusionsT-DXd is cost-effective based on surrogate WTP thresholds of €72,000 and €139,000 per QALY.

CDK4/6 Inhibitor Resistance in Hormone Receptor-Positive Metastatic Breast Cancer: Translational Research, Clinical Trials, and Future Directions.

The emergence of CDK4/6 inhibitors, such as palbociclib, ribociclib, and abemaciclib, has revolutionized the treatment landscape for hormone receptor-positive breast cancer. These agents have demonstrated significant clinical benefits in terms of both progression-free survival and overall survival. However, resistance to CDK4/6 inhibitors remains a challenge, limiting their long-term efficacy. Understanding the complex mechanisms driving resistance is crucial for the development of novel therapeutic strategies and the improvement of patient outcomes. Translational research efforts, such as preclinical models and biomarker studies, offer valuable insight into resistance mechanisms and may guide the identification of novel combination therapies. This review paper aims to outline the reported mechanisms underlying CDK4/6 inhibitor resistance, drawing insights from both clinical data and translational research in order to help direct the future of treatment for hormone receptor-positive metastatic breast cancer.

Prediction of bone metastasis risk of early breast cancer based on nomogram of clinicopathological characteristics and hematological parameters.

The purpose of this study was to determine the independent risk factors for bone metastasis in breast cancer and to establish a nomogram to predict the risk of bone metastasis in early stages through clinicopathological characteristics and hematological parameters. We selected 1042 patients with breast cancer from the database of Shandong Cancer Hospital for retrospective analysis, and determined independent risk factors for bone metastatic breast cancer (BMBC). A BMBC nomogram based on clinicopathological characteristics and hematological parameters was constructed using logistic regression analysis. The performance of the nomograph was evaluated using the receiver operating characteristic (ROC) and calibration curves. The clinical effect of risk stratification was tested using Kaplan-Meier analysis. BMBC patients were found to be at risk for eight independent risk factors based on multivariate analysis: age at diagnosis, lymphovascular invasion, pathological stage, pathological node stage, molecular subtype, platelet count/lymphocyte count, platelet count * neutrophil count/lymphocyte count ratio, Systemic Immunological Inflammation Index, and radiotherapy. The prediction accuracy of the BMBC nomogram was good. In the training set, the area under the ROC curve (AUC) was 0.909, and in the validation set, it was 0.926, which proved that our model had good calibration. The risk stratification system can analyze the risk of relapse in individuals into high- and low-risk groups. The proposed nomogram may predict the possibility of breast cancer bone metastasis, which will help clinicians optimize metastatic breast cancer treatment strategies and monitoring plans to provide patients with better treatment.

Living with metastatic breast cancer (LIMBER): experiences, quality of life, gaps in information, care and support of patients in the UK

PurposeTo determine the experiences, information, support needs and quality of life of women in the UK living with metastatic breast cancer (MBC) to provide content for educational materials.MethodsAn online survey, hosted for 3 months on a UK MBC charity website, comprised sections covering issues such as communication about MBC treatment and management, helpful and less helpful things that healthcare professionals, family and friends did or said and completion of the Patient Roles and Responsibilities Scale (PRRS).ResultsA total of 143 patients participated; 48/143(33%) presented de novo; 54/143(38%) had been living with MBC > 2 years. PRRS analysis revealed that MBC imposed a serious impact upon most respondents’ own caring abilities and social lives. A majority 98/139 (71%) wished they had known more about MBC before their diagnosis; 63/134(47%) indicated that they still did not fully understand their illness; merely 78/139(56%) had access to a specialist nurse and only 69/135(51%) had been offered any additional support. Respondents reported little consideration given to their lifestyle/culture during consultations and inconsistent information, support services, continuity of care or access to clinical trials. They commented upon things health care professionals/friends and family did or said that were useful and cited other behaviours that were especially unhelpful.ConclusionsMBC exerted a deleterious impact upon patients’ activities of daily living which were exacerbated in part by significant gaps in support, communication and information.Implications for cancer survivorsLIMBER results are informing the content of educational materials currently being developed for patients’ formal and informal carers.

Enzyme/pH dual stimuli-responsive nanoplatform co-deliver disulfiram and doxorubicin for effective treatment of breast cancer lung metastasis

ABSTRACT Objectives Metastasis is still one of the main obstacles in the treatment of breast cancer. This study aimed to develop disulfiram (DSF) and doxorubicin (DOX) co-loaded nanoparticles (DSF-DOX NPs) with enzyme/pH dual stimuli-responsive characteristics to inhibit breast cancer metastasis. Methods DSF-DOX NPs were prepared using the amphiphilic poly(ε-caprolactone)-b-poly(L-glutamic acid)-g-methoxy poly(ethylene glycol) (PCL-b-PGlu-g-mPEG) copolymer by a classical dialysis method. In vitro release tests, in vitro cytotoxicity assay, and anti-metastasis studies were conducted to evaluate pH/enzyme sensitivity and therapeutic effect of DSF-DOX NPs. Results The specific pH and enzyme stimuli-responsiveness of DSF-DO NPs can be attributed to the transformation of secondary structure and the degradation of amide bonds in the PGlu segment, respectively. This accelerated drug release significantly increased the cytotoxicity to 4T1 cells. Compared with the control group, the DSF-DOX NPs showed a strong inhibition of in vitro metastasis with a wound healing rate of 36.50% and a migration rate of 18.39%. Impressively, in vivo anti-metastasis results indicated that the metastasis of 4T1 cells was almost completely suppressed by DSF-DOX NPs. Conclusion DSF-DOX NPs with controllable tumor site delivery of DOX and DSF were a prospectively potential strategy for metastatic breast cancer treatment.

Estimating the Product Lifecycle Value of Trastuzumab Based on Registry Data in Sweden.

Trastuzumab was introduced in Sweden in 2000 for treatment of HER2-positive metastatic breast cancer (MBC) and later expanded to early breast cancer (EBC). The potential value of this innovative therapy was explored in economic evaluations; however, the extent to which these benefits were realised remains unknown. This study aims to estimate the lifecycle value of trastuzumab by combining randomised trial data with Swedish routine-care data. Trastuzumab impact on costs and health outcomes was estimated with Markov models for MBC and EBC. Model inputs included progression/recurrence and breast cancer-related mortality data from international randomised clinical trials, and Sweden-specific non-breast cancer-related mortality, numbers treated, and costs and utilities based on data from National Registries and literature. Model predictions were validated by observed survival rates from the National Breast Cancer Registry. From 2000 to 2021, 3936 and 11,134 patients with HER2-positive MBC and EBC, respectively, were treated with trastuzumab, resulting in 25,844 life years and 13,436per quality-adjusted life years (QALY) gained. Cost per QALY gained was lower in EBC (Swedish krona [SEK]285,000/QALY) than MBC (SEK554,000/QALY). The net-monetary value delivered (excluding drug costs) was SEK 13.714 billion, and society retained 62% of this. The modelled survival in trastuzumab-treated patients with EBC matched closely with actually observed survival in registry data. Trastuzumab provided substantial population-level health benefits for patients and society, with favourable cost effectiveness in MBC and EBC. There is some uncertainty around the magnitude of these benefits, mainly due to missing data on health outcomes and number of treated patients with MBC.

Real World Experience of Second-Line Treatment Strategies after Palbociclib and Letrozole: Overall Survival in Metastatic Hormone Receptor-Positive Human Epidermal Growth Factor Receptor 2-Negative Breast Cancer

Background: We analyzed real-world practice of second-line treatment in hormone receptor (HR)+ human epidermal growth factor receptor-2 (HER2)− metastatic breast cancer (MBC) following the first-line CDK4/6 inhibitor with letrozole. In addition, we evaluated the relationship between second-line treatment strategies and survival outcome. Methods: Using the clinical data warehouse, clinical information including MBC diagnosis, treatment and survival outcomes were collected. Results: In total, 305 patients were treated with the first-line palbociclib plus letrozole, and we evaluated 166 patients who were treated with second-line treatment. Of the 166 patients, 28.5% were treated with capecitabine (C), followed by exemestane with everolimus (EE) (27.3%) or cytotoxic chemotherapy other than capecitabine (T) (18.8%) and fulvestrant-based treatment or endocrine monotherapy (F) (12.7%). Eighteen patients (10.9%) were enrolled in clinical trials (CT). With regard to treatment strategies, and the median progression-free survival of second-line treatment in a metastatic setting (PFS2) was 7.4 months with C, 5.2 months with EE, 4.8 months with T, 3.6 months with F, and 3.6 months with CT (p = 0.066). In patients with visceral organ disease progression, C (31.3%) or T(31.3%) was the most common second-line treatment followed by EE (21.9%). Most of the 47 patients with bone metastasis alone were treated with EE (38.2%), followed by C (23.4%) and F (21.3%) (p = 0.008). The median overall survival of second-line treatment in a metastatic setting (OS2) was 42.3 months with C, 35.7 months with F, 30.7 months with EE, and 23.1 months with T. The median OS2 for those in CT was not reached (p = 0.064). ER driven BC, disease progression site and PFS2 were associated with OS and OS2 in HR+HER2− MBC (ps < 0.05). Conclusions: We suggested the second line treatment strategy was important to improve prognosis in patients with HR+/HER2− MBC, especially given the recent standardization of first-line treatment and the many available second-line options.

The аntitumor effect of 2-[3-(2-chloroethyl)-3-nitrosoureido]-1,3-propanediol (chlonisol) on the growth of spontaneous mammary tumors in HER-2/neu transgenic mice

Background. Current treatment of HER2-positive metastatic breast cancer (BC) is based on the use of anti-HER2 blockers as pathogenic drugs, as well as the search for the optimal combination of anticancer drugs with different mechanisms of action. The potential activity of chlonisol in HER2+ ВС is of great interesting. The aim of the study was to evaluate the antitumor effect of 2-[3-(2-chloroethyl)-3-nitrosouriedo]-1,3-propanediol (chlonisol) on the growth of spontaneous mammary tumors in HER-2/neu transgenic FVB/N mice. Material and Methods. A prospective study used 5-month-old female mice with HER2-positive mammary tumors. Of these animals, ten pairs with almost the same size of tumors were formed (respectively, for the control group and the chlonisol treatment group). Chlonisol was administered at a dose of 20 mg/kg intraperitoneally, once. The animals were followed up for 30 days. Results. In all ten pairs of mice, chlonisol showed a significant antitumor effect, up to a complete temporary regression of the tumor. When summing the comparative results of all ten pairs of animals, the inhibition of tumor growth (ITG) in the chlonisol treatment group was 90-97 % (p<0.0001), and the area under the kinetic curve of tumor growth was 13.6 times less than in the control group (p<0.0001), thus indicating a significant effect. Conclusion. Chlonisol has a high therapeutic activity by inhibiting the growth of spontaneous HER2-positive breast tumors in FVB/N mice.

Updated analysis – OlympiA study: Chance of cure in early and locally advanced gBRCA-associated breast cancer

PARP inhibitors have been successfully used in the treatment of BRCA-associated metastatic breast cancer in recent years. Adjuvant therapy for gBRCAm carriers with HER 2-negative high-risk early-stage breast cancer has become a new indication for the use of olaparib.This publication highlights the results of an updated analysis of the OlympiA trial that has changed clinical practice. Adjuvant treatment with olaparib for 1 year signifiantly increased survival rates. Four-year IDFS for the olaparib group was 82.7 % vs 75.4 % for placebo group.Four-year OS was 89.8 % in the olaparib group and 86.4 % in the placebo group. The treatment has a favorable safety profie and does not reduce quality of life. Despite impressive results the OlympiA study raises many questions about the possibilities of integrating PARP inhibitors into modern standards for the treatment of early breast cancer. The main points of contention and possible ways to resolve them are discussed in this review.

Metastatic breast cancer in Kenya: survival, prognosis and management at a tertiary referral centre.

There has been an increase in breast cancer in Africa with up to 77% of patients diagnosed with advanced disease. However, there is little data on survival outcomes and prognostic factors affecting survival in patients with metastatic breast cancer (MBC) in Africa. The study objective was to establish the survival of patients with MBC at a single tertiary health facility, the clinical and pathological characteristics affecting survival and describe the treatment modalities used. This was a retrospective descriptive study conducted at Aga Khan University Hospital, Nairobi of patients diagnosed with MBC between 2009 and 2017. Survival data was collected on metastatic free survival, survival time between diagnosis of first metastasis and death and overall survival. Data on patient's age, menopausal status and stage at diagnosis, tumour grade, receptor status, site of metastasis and treatment given was also collected. The Kaplan-Meier Estimator was used to estimate survival. Prognostic factors for survival outcomes were analysed using univariate analysis. Standard descriptive statistics were used to describe patient characteristics. A total of 131 patients were included in the study. The median survival was 22 months. The 3 and 5-year survivals were 31.3% and 10.7%, respectively. On univariate analysis, the Luminal A molecular subtype was a significant positive prognostic factor hazard ratios (HR 0.652 95% confidence interval (CI) 0.473-0.899) while metastasis to the liver or brain were significant negative prognostic factors (HR 0.615 95% CI 0.413-0.915 and HR 0.566 95% CI 0.330-0.973, respectively). A large proportion (87.0%) received some treatment for metastatic disease. Our study concluded that survival rates for patients diagnosed with MBC were lower compared to studies from Western countries but higher than in studies from Sub-Saharan Africa. Luminal A molecular subtype was found to be a positive prognostic factor and metastasis to the liver or brain were found to be negative prognostic factors. Improved access to adequate treatment for MBC is required in the region.

Impact of Race and Area Deprivation on Triple-Negative Metastatic Breast Cancer Outcomes.

To describe area deprivation, anxiety, depression, relative dose intensity of first-line metastatic breast cancer (MBC) treatment, and survival in Black and White women who had died from triple-negative MBC, including interaction analysis. This cohort study drew from a database of women who had died from MBC (N = 53). Descriptive statistics, independent t tests, analysis of variance, and Mann-Whitney U tests were used, and effect sizes were calculated. Compared with White women, Black women reported higher anxiety and depression at MBC baseline. Black women living in areas of higher deprivation experienced shorter overall survival than White women living in similar areas (9.9 months versus 24.6 months). These results were not statistically significant, likely because of a small sample size, but were clinically meaningful. Black and low-income women with breast cancer experience inferior survival as compared with White and higher-income women. Newer explanatory models for racial disparity in cancer outcomes include the assessment of neighborhood deprivation. White women may be less affected by their neighborhood, even when living in areas of greater deprivation influencing cancer outcomes. This merits further exploration.

Update on Classic and Novel Approaches in Metastatic Triple-Negative Breast Cancer Treatment: A Comprehensive Review.

Triple-negative breast cancer (TNBC) accounts for almost 15% of all diagnosed breast cancers and often presents high rates of relapses and metastases, with generally poor prognosis despite multiple lines of treatment. Immunotherapy has radically changed the approach of clinicians towards TNBC in the last two to three years, even if targeted and specific therapeutic options are still missing; this unmet need is further justified by the extreme molecular and clinical heterogeneity of this subtype of breast cancer and by the weak response to both single-agent and combined therapies. In March 2023, the National Comprehensive Cancer Network (NCCN), the main association of cancer centers in the United States, released the last clinical practice guidelines, with an update on classic and novel approaches in the field of breast cancer. The purpose of this comprehensive review is to summarize the latest findings in the setting of metastatic TNBC treatment, focusing on each category of drugs approved by the Food and Drug Administration (FDA) and included in the NCCN guidelines. We also introduce part of the latest published studies, which have reported new and promising molecules able to specifically target some of the biomarkers involved in TNBC pathogenesis. We searched the PubMed and Scopus databases for free full texts reported in the literature of the last 5 years, using the words "triple-negative breast cancer" or "TNBC" or "basal-like". The articles were analyzed by the authors independently and double-blindly, and a total of 114 articles were included in the review.

PD-1/PD-L1 immune checkpoint inhibitors in metastatic triple-negative breast cancer: a systematic review and meta-analysis.

PD-1/PD-L1 immune checkpoint inhibitors (ICIs) have been controversial in the treatment of metastatic triple negative breast cancer (mTNBC). We collected randomized controlled trials in accordance with the study and carried out meta-analysis to comprehensively evaluate the efficacy and safety of immune checkpoint inhibitors in mTNBC. To systematically evaluate the efficacy and safety of PD-1/PD-L1 ICIs (hereinafter referred to as ICIs) in the treatment of mTNBC. As of 2023.2.5, Medline, PubMed, Embase, Cochrane library database and Web of Science were searched to determine the study in accordance with the trial of ICIs in the treatment of mTNBC. The assessment endpoints included objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety. Meta-analysis of the included studies was performed using Revman 5.4. A total of six trials with 3172 patients were included in this meta-analysis. The ORR of ICIs combined with chemotherapy was significantly improved compared with chemotherapy (HR=0.88, 95%CI: 0.81-0.94, I2=0%). For PFS, the experimental group were better than the control group in both intention-to-treat (ITT) population and PD-L1 positive population, showing statistical significance (ITT: HR=0.81, 95%CI: 0.74-0.89, P<0.05, I2=0%; PD-L1 positive: HR=0.72, 95%CI: 0.63-0.82, P<0.05, I2=18%); For OS, in the ITT population, no statistical difference was observed in either ICIs combined with chemotherapy(HR=0.92, 95%CI: 0.83-1.02, P=0.10)or immune monotherapy(HR=0.78, 95%CI: 0.44-1.36, P=0.37), in the PD-L1 positive population, ICIs group had better OS than chemotherapy group (HR=0.83, 95%CI: 0.74-0.93, P < 0.05); In safety, serious adverse event (SAE) was no statistically significant difference between the ICIs group and the chemotherapy group; however, the incidence of immune-related adverse event (irAE) was significantly higher in the ICIs group than in the chemotherapy group (HR=2.15, 95%CI: 1.45-3.19, P < 0.05). ICIs combined with chemotherapy significantly improved the PFS of mTNBC, however, ICIs only improved the OS in PD-L1 positive people, and no statistical difference was observed in ITT population; while benefiting from ICIs, we found that irAE in ICIs group increased significantly, and its high rate of adverse events still needs to be taken seriously.

Impact of Nanomedicine in Women's Metastatic Breast Cancer.

Metastatic breast cancer is responsible for 90% of mortalities among women suffering from various types of breast cancers. Traditional cancer treatments such as chemotherapy and radiation therapy can cause significant side effects and may not be effective in many cases. However, recent advances in nanomedicine have shown great promise in the treatment of metastatic breast cancer. For example, nanomedicine demonstrated robust capacity in detection of metastatic cancers at early stages (i.e., before the metastatic cells leave the initial tumor site), which gives clinicians a timely option to change their treatment process (for example, instead of endocrine therapy they may use chemotherapy). Here recent advances in nanomedicine technology in the identification and treatment of metastatic breast cancers are reviewed.

Mechanisms of Resistance to Antibody-Drug Conjugates.

The treatment of cancer patients has dramatically changed over the past decades with the advent of monoclonal antibodies, immune-checkpoint inhibitors, bispecific antibodies, and innovative T-cell therapy. Antibody-drug conjugates (ADCs) have also revolutionized the treatment of cancer. Several ADCs have already been approved in hematology and clinical oncology, such as trastuzumab emtansine (T-DM1), trastuzumab deruxtecan (T-DXd), and sacituzumab govitecan (SG) for the treatment of metastatic breast cancer, and enfortumab vedotin (EV) for the treatment of urothelial carcinoma. The efficacy of ADCs is limited by the emergence of resistance due to different mechanisms, such as antigen-related resistance, failure of internalization, impaired lysosomal function, and other mechanisms. In this review, we summarize the clinical data that contributed to the approval of T-DM1, T-DXd, SG, and EV. We also discuss the different mechanisms of resistance to ADCs, as well as the ways to overcome this resistance, such as bispecific ADCs and the combination of ADCs with immune-checkpoint inhibitors or tyrosine-kinase inhibitors.

EE260 Cost-Effectiveness Analysis of Sacituzumab Govitecan As Second-Line Treatment for Metastatic Triple-Negative Breast Cancer in Japan

Single-agent chemotherapy is the standard treatment for metastatic triple-negative breast cancer (mTNBC), but its efficacy is unsatisfactory. Although sacituzumab govitecan (SG) showed superiority over chemotherapy in improving overall survival, it is not approved in Japan and its cost-effectiveness is not necessarily clear. This study aimed to evaluate the cost-effectiveness of SG from the payer’s perspective in Japan.

PCR220 Symptom Burden in Late-Stage Breast Cancer Patients Treated with CDK Inhibitors Using the PRO-CTCAE

Cyclin-Dependent Kinase Inhibitors (CDKI) are an important advancement in the treatment of Metastatic Breast Cancer. Barriers to clinician adoption, such as tolerability concerns, may limit front line use. The objective of this study is to use electronic patient-reported outcome (ePRO) and remote symptom monitoring platform to evaluate symptom differences among late-stage breast cancer patients with and without CDKI treatment.

Real-World Outcomes of CDK4/6 Inhibitors Treatment in Metastatic Breast Cancer in Romania.

The introduction in clinical practice of selective cyclin-dependent kinase (CDK) 4/6 inhibitors improves the outcome of patients with hormone receptor (HR)-positive human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (mBC). In Romania, the three available CDK 4/6 inhibitors (Palbociclib, Ribociclib and Ademaciclib) have been approved by the National Agency for Medicines (ANM) in 2019, 2020 and 2021. We conducted a retrospective study from 2019 to 2022 on 107 patients with metastatic breast cancer HR+ that have been treated with CDK 4/6 inhibitors in addition to hormone therapy in the Oncology Department of Colțea Clinical Hospital in Bucharest. The purpose of this study is to calculate the median progression-free survival (PFS) and to compare it with the median PFS from other randomized clinical trials. A key difference from other studies is that our study evaluated both patients with non-visceral mBC and patients with visceral mBC, as these two groups often have different outcomes. A total of 79.4% were postmenopausal patients and 20.6% were premenopausal; 42.1% had different stages at the beginning of disease and 57.9% presented newly metastatic disease. Median PFS was 17 months, unlike randomized clinical trials which reported a median PFS of 25.3 months. The combination of CDK 4/6 inhibitors with endocrine therapy is the golden standard treatment in HR-positive, HER2-negative metastatic breast cancer, bringing a prolongation of survival for these patients. Our results show no major differences compared to randomized clinical trials, despite the smaller patient group. In order to have a picture of the efficacy of the treatment as close as possible to the real-world data, we believe that it would be very useful to have a collaboration between several oncology departments in different institutions to carry out a multi-center study on large groups of patients.

Body composition measures as predictors of toxicity in patients with metastatic breast cancer receiving PARP inhibitors.

e13010 Background: Poor body composition metrics (BCM), such as high adiposity or low muscle mass, are associated with inferior cancer outcomes. Poly ADP-ribose polymerase inhibitors (PARPi) revolutionized the treatment of metastatic breast cancer (MBC) with germline BRCA mutation but can cause substantial toxicity. The recommended dose of PARPi is fixed and neither weight nor BCM are taken into consideration during initial prescription or during dose reductions. We aimed to investigate the association between BCM and toxicity and tolerability to PARPi in MBC patients. Methods: We identified all MBC patients treated with PARPi between 2015-2022 at Tel Aviv Sourasky Medical Center. Using computerized tomography (CT) images taken for the evaluation of disease burden, BCM such as: skeletal muscle area (SMA) and subcutaneous adipose tissue area (SAT), were measured at the level of the third lumbar (L3) vertebrae. Low SMA was defined as &lt; 107.2 cm2 and low SAT was defined as &lt; 190 cm2. Receiver operating characteristic (ROC) curves were used to define these thresholds. Sarcopenia was defined as skeletal muscle index (SMI = SMA/height2) &lt; 41 based on literature. Fisher exact tests and Mann-Whitney U tests were used for statistical analyses. Results: We identified 30 patients with MBC who were treated with PARPi and met the study requirements at a median age of 54 (range 29-87). Median duration of PARPi treatment was 214 days (range 35-921). Among them, 19 (63%) were sarcopenic, 22 (73%) had low SMA, 10 (33%) had low SAT and 17 (57%) suffered from Grade 2-4 adverse events (AE). Patients with sarcopenia had non-significantly more Grade 3-4 AE (42% vs. 18%) and more dose reduction or dose delay events (42% vs. 27%) compared to non-sarcopenic patients. Patients with low SMA had borderline significantly more Grade 3-4 AE, dose reduction or dose delay events (55% vs. 13%, p = 0.065), compared to patients with high SMA. Patients with low SAT had significantly more Grade 3-4 AE (60% vs 20%, P = 0.036), compared to patients with high SAT. Moreover, patients with Grade 2-4 AE had significantly lower SAT compared with patient with &lt; Grade 2 AE (median 183 vs. 298 cm2, p = 0.008). Conclusions: Our study implies an association between BCM and PARPi toxicity and tolerability. Skeletal muscle mass and adipose tissue may be taken into consideration in PARPi treatment and dosing decisions. A larger study is needed to further examine this hypothesis.

Subcellular Organelle-Targeted Nanostructured Lipid Carriers for the Treatment of Metastatic Breast Cancer.

Subcellular organelle targeted nano-formulations for cancer treatment are receiving increasing attention owing to their benefits of precise drug delivery, maximized therapeutic index, and reduced off-target side effects. The nucleus and mitochondria, as the main subcellular organelles, are the significant organelles responsible for maintaining cell operation and metabolism. They can be involved in many essential physiological and pathological processes such as cell proliferation, organism metabolism, intracellular transportation, and play a critical role in regulating cell biology. Meanwhile, breast cancer metastasis is one of the leading causes of death in breast cancer patients. With the development of nanotechnology, nanomaterials have been widely used in tumor therapy. We designed a subcellular organelle targeted nanostructured lipid carriers (NLC) to deliver paclitaxel (PTX) and gambogic acid (GA) to tumor tissues. Due to the surface of NLC being modified by subcellular organelle targeted peptide, the PTX and GA co-loaded NLC can accurately release PTX and GA in tumor cells. This property makes NLC able to easy to enter tumor site and target the specific subcellular organelle. The modified NLC can efficiently inhibit the growth of 4T1 primary tumor and lung metastasis, which may be related to the down-regulation of matrix metalloproteinase-9 (MMP-9) and BCL-2 levels, up-regulation of E-cadherin level, and antagonized PTX-induced increase of C-C chemokine ligand 2 (CCL-2) levels by GA. Meanwhile, the synergistic anti-tumor effect of GA and PTX has also been verified in vitro and in vivo experiments. The subcellular organelle targeted peptide modified PTX+GA multifunctional nano-drug delivery system has a good therapeutic effect on tumors, and this study provides significant insights into the role of different subcellular organelles in inhibiting tumor growth and metastasis and inspires researchers to develop highly effective cancer therapeutic strategies through subcellular organelle targeted drugs.