Therapy For Metastatic Breast Cancer Research Articles

An Overview of Receptor-targeted Nanotechnological Approaches for the Treatment of Metastatic Breast Cancer

Abstract: Breast cancer (BC) is the second most prevalent cancer among women and can originate from the tubes, connective tissue, and lobules of the breast. The primary focus of this review is to highlight the significant advancement in the development of receptor-targeted nanotherapy for the management of metastatic breast cancer. These innovative systems directly target the specific cancer cell receptor to enhance the precision and effectiveness of the treatment. Inadequate therapy and incorrect diagnosis in conventional treatment have contributed to the rising mortality rate from breast cancer. BC that has spread to another organ in the body, commonly called Metastatic breast cancer (MBC) or Stage IV metastases, is an aggressive and heterogeneous illness that decreases the prognosis. The current treatment methods for MBC are similar to initial-stage breast cancer, which involve hormonal surgery, chemotherapy, immunotherapy, and radiation therapy with poor specificity and invasive. Moreover, treating MBC is more difficult because the cancer cells varies depending on the organ. Nanotechnology provides valuable insights for treating MBC that enable the early identification of tumor cells. Moreover, it can also transport therapeutic agents directly to the targeted sites while reducing the toxicity to healthy tissue. Due to its multifunctional, programmable, and trackable properties, future research and treatment may succeed with nanotechnology-based imaging and therapy. The present study summarizes an overview of nanotechnology-based drug delivery methods (NDDM) and receptor-targeting nanotherapy (RTN) that are applied in MBC therapy to gain attention in clinical applications. Clinical trial studies have also been discussed along with receptor-targeting nanomedicine and the status of the most relevant patent.

Impact of trastuzumab emtansine (T-DM1) on spleen volume in patients with HER2-positive metastatic breast cancer.

Trastuzumab emtansine (T-DM1) is a novel therapy for human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer, combining the targeted action of trastuzumab with the cytotoxic effects of emtansine. Although T-DM1 has demonstrated greater efficacy and safety compared to traditional therapies, concerns about hepatotoxicity and spleen-related complications have arisen. We conducted a retrospective study of 64 HER2-positive metastatic breast cancer patients treated with T-DM1 at our institution. Patients underwent computed tomography or magnetic resonance imaging at baseline and during treatment cycles. Spleen volume, portal vein diameter, and laboratory values were compared between baseline and 12months after T-DM1 treatment. Median spleen volume significantly increased from 201cm3 (IQR, 157-275) at baseline to 291cm3 (IQR, 215-420) after 12months of T-DM1 treatment (P<0.001). Spleen enlargement was observed in 87.5% of patients, while no significant alteration was detected in portal vein diameter. The change in spleen volume was positively correlated with changes in serum globulin levels, liver enzymes, and bilirubin levels, but did not impact survival outcomes. T-DM1 therapy in HER2-positive metastatic breast cancer leads to significant spleen enlargement and systemic biochemical changes. Future studies should focus on elucidating the long-term implications of these findings and optimizing monitoring strategies for spleen-related complications.

Trastuzumab Deruxtecan after Endocrine Therapy in Metastatic Breast Cancer.

Outcomes in patients with hormone receptor-positive metastatic breast cancer worsen after one or more lines of endocrine-based therapy. Trastuzumab deruxtecan has shown efficacy in patients with metastatic breast cancer with low expression of human epidermal growth factor receptor 2 (HER2) after previous chemotherapy. We conducted a phase 3, multicenter, open-label trial involving patients with hormone receptor-positive metastatic breast cancer with low HER2 expression (a score of 1+ or 2+ on immunohistochemical [IHC] analysis and negative results on in situ hybridization) or ultralow HER2 expression (IHC 0 with membrane staining) who had received one or more lines of endocrine-based therapy and no previous chemotherapy for metastatic breast cancer. Patients were randomly assigned in a 1:1 ratio to receive trastuzumab deruxtecan or the physician's choice of chemotherapy. The primary end point was progression-free survival (according to blinded independent central review) among the patients with HER2-low disease. Secondary end points included progression-free survival among all the patients who had undergone randomization, overall survival, and safety. Of the 866 patients who underwent randomization, 713 had HER2-low disease, and 153 had HER2-ultralow disease. Among the patients with HER2-low disease, the median progression-free survival was 13.2 months (95% confidence interval [CI], 11.4 to 15.2) in the trastuzumab deruxtecan group and 8.1 months (95% CI, 7.0 to 9.0) in the chemotherapy group (hazard ratio for disease progression or death, 0.62; 95% CI, 0.51 to 0.74; P<0.001); the results were consistent in the exploratory HER2-ultralow population. Data for overall survival were immature. Adverse events of grade 3 or higher occurred in 52.8% of the patients in the trastuzumab deruxtecan group and in 44.4% of those in the chemotherapy group. Adjudicated interstitial lung disease or pneumonitis occurred in 49 patients (11.3%; three events were grade 5 in severity) and in 1 patient (0.2%; grade 2), respectively. Among patients with hormone receptor-positive, HER2-low or HER2-ultralow metastatic breast cancer who had received one or more lines of endocrine-based therapy, treatment with trastuzumab deruxtecan resulted in longer progression-free survival than chemotherapy. No new safety signals were identified. (Funded by AstraZeneca and Daiichi Sankyo; DESTINY-Breast06 ClinicalTrials.gov number, NCT04494425.).

416P Prognostic impact of liquid biopsy (LB) biomarkers at relapse on second-line (2L) treatment (Tx) after progression to endocrine therapy (ET) in metastatic breast cancer (mBC): Ancillary analysis of the MAGNETIC.1 study

416P Prognostic impact of liquid biopsy (LB) biomarkers at relapse on second-line (2L) treatment (Tx) after progression to endocrine therapy (ET) in metastatic breast cancer (mBC): Ancillary analysis of the MAGNETIC.1 study

Cost-effectiveness of early vs delayed use of abemaciclib combination therapy for patients with high-risk hormone receptor-positive/human epidermal growth factor receptor 2-negative early breast cancer.

Abemaciclib was newly approved for hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) high-risk early breast cancer (EBC). Clinical guidelines recommended abemaciclib as the first-line treatment for HR+/ HER2- EBC (early use) or HR+/ HER2- metastatic breast cancer (MBC) (delayed use). To compare the cost-effectiveness of early vs delayed use of abemaciclib for treatment of HR+/HER2- high-risk EBC. Early use was defined as combined abemaciclib and endocrine therapy as first-line therapy for EBC, followed by treatment with fulvestrant for MBC. Delayed use was defined as endocrine therapy for EBC, followed by combined abemaciclib and fulvestrant therapy for MBC. A 5-state model was developed to estimate lifetime costs, life-years (LYs), and quality-adjusted life-years (QALYs) of hypothetical patients with HR+/ HER2- EBC from a third-party US payer's perspective. Key clinical and safety data were derived from the monarchE and MONARCH 2 clinical trials. Costs, utilities, and disutility values of adverse events were obtained from the literature. We calculated the incremental cost-effectiveness ratio (ICER) of early vs delayed abemaciclib use and compared it with a willingness-to-pay (WTP) threshold of $100,000 per LY or QALY. Deterministic and probabilistic sensitivity analyses (PSAs) were performed to test the robustness of the base-case model. Base-case analysis showed early use yielded 21.08 LYs and 17.93 QALYs for $586,213 and delayed use yielded 11.14 LYs and 9.38 QALYs for $157,576. The ICER of early vs delayed use was $43,136/LY and $50,104/QALY, which was cost-effective at the WTP threshold of $100,000. The PSA result indicated that a 94.6% likelihood of early use (vs delayed use) was cost-effective at the WTP threshold of $100,000 per QALY. This study suggests that giving abemaciclib in the early stage rather than waiting until patients develop metastatic disease (current standard of care in MBC) is a cost-effective strategy.

Eganelisib combined with immune checkpoint inhibitor therapy and chemotherapy in frontline metastatic triple-negative breast cancer triggers macrophage reprogramming, immune activation and extracellular matrix reorganization in the tumor microenvironment

BackgroundTriple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with a poor prognosis particularly in the metastatic setting. Treatments with anti-programmed cell death protein-1/programmed death-ligand 1 (PD-L1) immune...

P98. Stereotactic radiation therapy and spine surgery for metastatic breast cancer to the spine are associated with 1-, 2-, and 5-year mortality rates

P98. Stereotactic radiation therapy and spine surgery for metastatic breast cancer to the spine are associated with 1-, 2-, and 5-year mortality rates

17 CDK4/6 inhibition with Abemaciclib in in patients (pts) with previously treated advanced renal carcinoma (RCC)

Abstract Background Preclinical data suggests rationale for CDK4/6 alone and in combination with HIF-2 inhibitors; single agent activity for CDK4/6 inhibitors in RCC has not been reported. Abemaciclib is an oral CDK4/6 inhibitor approved in combination with hormonal therapy for metastatic breast cancer. In our phase 1b clinical trial (NCT04627064), we investigated the safety and clinical efficacy of abemaciclib monotherapy in pts with advanced pretreated RCC with clear cell component. Methods In this single center trial, adult pts with advanced RCC with a clear cell component and ECOG status of ≤1 progressing after at least one prior regimen including immunotherapy and a VEGF TKI received abemaciclib 200 mg twice daily in 4-week cycles until progression or unacceptable toxicity. Primary objective was to evaluate the objective response rate (ORR) of abemaciclib with secondary endpoint of safety. First imaging was performed after 2 cycles. Response assessed per RECIST 1.1 and toxicity per CTCAE v5.0. Results 11 pts (10 clear cell RCC and 1 translocation RCC) were enrolled between 12/31/2020 and 10/03/2023. Median age was 62 years (range 54-68) with 18% (n=2) showing sarcomatoid features. 73% (n=8) had IMDC intermediate risk disease and one patient had translocation RCC (tRCC) with a clear cell component. Median number of prior therapies was 4 (range 1-9). Seven patients received 2 cycles and 4 patients received &amp;lt; 2 cycles. ORR was 0% (0/11; 8 progressive disease, 1 stable disease in tRCC stopping for clinical progression, 2 pts not evaluable with clinical progression). 27% (n=3) experienced grade ≥3 treatment-related adverse events (diarrhea n=1, nausea n=1, neutropenia n=1). Conclusions In pts with heavily pretreated RCC, abemaciclib had manageable toxicity profile but no clinically meaningful activity as monotherapy. This data will offer important insight into interpretation of results for ongoing trials exploring CDK4/6 inhibition in combination with HIF-2 inhibitors.

Concurrent Use of Trastuzumab Deruxtecan and Radiation Therapy in HER2-positive and HER2-low Metastatic Breast Cancer: A Single-center Experience and Review of the Literature.

Recent DESTINY-Breast trials have demonstrated trastuzumab deruxtecan's effectiveness in HER2-positive and HER2-low metastatic breast cancer. However, safety concerns remain regarding its combination with radiation therapy (RT). The purpose of this work is to assess the toxicity profile of combining trastuzumab deruxtecan and RT in patients with HER2-positive and HER2-low metastatic breast cancer to address these concerns. We conducted a retrospective study which included patients treated at Institut Curie Paris between November 2020 and January 2024. Patients with HER2-positive and HER2-low metastatic breast cancer who received concurrent trastuzumab deruxtecan and RT were identified. Data on patient demographics, treatment regimens, radiation doses, toxicity profiles, and treatment discontinuations were collected. Follow-up was conducted from the last day of radiotherapy until death or the last examination and toxicities were graded using the CTCAE V5.0. The studied population includes all 33 patients with HER2-positive and HER2-low metastatic breast cancer who underwent concurrent treatment with trastuzumab deruxtecan and radiotherapy. The median follow-up was 11 months. The most common acute grade 1 toxicity was nausea. Grade 2 toxicities affected 21.2% of patients, including asthenia, mucositis, cardiac decompensation, and diarrhea. Trastuzumab deruxtecan discontinuation occurred in 5 patients due to systemic treatment-related toxicities, including nausea, thrombocytopenia, neutropenia, and cardiac decompensation. There were 21.2% reported with late toxicities, with nausea being the most prevalent. Our series of patients who received concurrent treatment of radiotherapy and trastuzumab deruxtecan are showing acceptable toxicity. Larger prospective studies are needed to evaluate the toxicity and efficacy of this combination.

Identification of peripheral blood test parameters predicting the response to palbociclib and endocrine therapy for metastatic breast cancer: a retrospective study in a single institution.

Cyclin-dependent kinase 4/6 inhibitors have been used in endocrine therapy for patients with estrogen receptor (ER)-positive and human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer. Although randomized trials have shown that combined therapies prolong progression-free survival (PFS) in comparison to endocrine monotherapy, the predictors of efficacy are unknown. This study aimed to identify the blood test parameters to predict the effects of palbociclib and endocrine therapy. Seventy-nine patients treated with palbociclib and endocrine therapy between December 2017 and June 2022 were reviewed. We assessed PFS in patients according to factors evaluated based on patient characteristics and peripheral blood tests. Patients in the C-reactive protein (CRP)-high, lactate dehydrogenase (LDH)-high, and albumin (Alb)-low groups had significantly shorter PFS than those in the normal group. A multivariate analysis revealed that high LDH and low Alb levels were independent factors that affected PFS. The Alb-low group had an inferior disease control rate. Patients in the CRP-high, LDH-high, and Alb-low groups who received these therapies as first- or second-line treatments showed poor PFS. Several predictors of the efficacy of palbociclib and endocrine therapy were identified in the peripheral blood test parameters of patients with ER-positive and HER2-negative subtypes of metastatic breast cancer.

Prognostic Significance of Pan-Immune-Inflammation Value in Patients with HER2-Positive Metastatic Breast Cancer Treated with Trastuzumab Emtansine.

Trastuzumab emtansine (T-DM1) is a mainstay therapy for HER2-positive metastatic breast cancer (mBC). However, identifying patients who will benefit most remains a challenge due to the lack of reliable biomarkers. The recently developed pan-immune-inflammation value (PIV), a novel immune-inflammation marker, could aid in this regard, considering the immunomodulatory effects of T-DM1. Therefore, we aimed to evaluate the association between the PIV and the efficacy of T-DM1 in patients with HER2-positive mBC. A total of 122 HER2-positive mBC patients treated with T-DM1 were included. Receiver operating characteristic (ROC) curve analyses were conducted to determine the optimal PIV threshold value for survival prediction. Kaplan-Meier survival curves and Cox regression analyses were used for univariable and multivariable survival analyses, respectively. The median age was 51 years, and 95.1% of the patients had ECOG PS 0-1. The optimal PIV cutoff value was identified as 338 in ROC analyses (AUC: 0.667, 95% CI: 0.569-0.765, p = 0.002). The multivariate analysis revealed that patients in the high-PIV group had significantly shorter OS (HR: 2.332; 95% CI: 1.408-3.861; p = 0.001) and PFS (HR: 2.423; 95% CI: 1.585-3.702; p < 0.001) than patients in the low-PIV group. Additionally, both ORR and DCR were significantly lower in the high-PIV group (36.6% vs. 61.3%, p = 0.011; 56.1% vs. 76.0%, p = 0.027). Our findings suggest that pre-treatment PIV may be a novel prognostic biomarker for HER2-positive mBC patients receiving T-DM1. A low PIV level is associated with more favorable outcomes. Future prospective studies are warranted to validate these findings and explore the potential utility of PIV in aiding treatment decisions.

Treatment-related adverse events in patients with advanced breast cancer receiving adjuvant AKT inhibitors: a meta-analysis of randomized controlled trials.

Incorporation of AKT inhibitors into adjuvant therapy for advanced or metastatic breast cancer has improved clinical outcomes. However, the safety of AKT inhibitors should be better evaluated, given the possibility of prolonging survival and impacting patient quality of life. Our aim was to assess how the addition of AKT inhibitors to adjuvant therapy affects treatment-related adverse events. We evaluated binary outcomes with risk ratios (RRs), with 95% confidence intervals (CIs). We used DerSimonian and Laird random-effect models for all endpoints. Heterogeneity was assessed using I2 statistics. R, version 4.2.3, was used for statistical analyses. A total of seven RCTs comprising 1619 patients with BC. The adverse effects that show significance statistical favoring the occurrence of adverse effects in AKT inhibitor were diarrhea (RR 3.05; 95% CI 2.48-3.75; p < 0.00001; I2 = 49%), hyperglycemia (RR 3.4; 95% CI 1.69-6.83; p = 0.00058; I2 = 75%), nausea (RR 1.69; 95% CI 1.34-2.13; p = 0.000008; I2 = 42%), rash (RR 2.79; 95% CI 1.49-5.23; p = 0.0013; I2 = 82%), stomatitis (RR 2.24; 95% CI 1.69-2.97; p < 0.00001; I2 = 16%) and vomiting (RR 2.99; 95% CI 1.85-4.86; p = 0.00009; I2 = 42%). There was no significant difference between the groups for alopecia (p = 0.80), fatigue (p = 0.087), and neuropathy (p = 0.363380). The addition of AKT inhibitors to adjuvant therapy was associated with an increase in treatment-related adverse events. These results provide safety information for further clinical trials evaluating AKT inhibitor therapy for patients with metastatic BC. Clinicians should closely monitor patients for treatment-related adverse events to avoid discontinuation of therapy and morbidity caused by these early-stage therapies.

Real-world Outcomes of Dual HER2 Blockade Therapy in Metastatic HER2-Positive Breast Cancer: from Induction to Maintenance.

Dual human epidermal growth factor receptor 2 (HER2) blockade with trastuzumab and pertuzumab combined with taxane-based chemotherapy (Cht) has been the standard first-line treatment for HER2-positive metastatic breast cancer (mBC) for years, due to the impressive results of the CLEOPATRA study. Real-world (RW) studies have become critical for assessing treatment effectiveness and safety in real-life circumstances. The aim of this study was to analyze the treatment outcomes of first-line therapy for HER2-positive mBC in RW clinical practice, specifically focusing on the use of maintenance endocrine therapy (ET) in hormone receptor positive (HR-positive) patients. This retrospective analysis included 106 HER2-positive mBC patients treated with trastuzumab and pertuzumab combined with taxane-based Cht from October 2015 to December 2020 at the University Hospital Centre Zagreb. At a median follow-up of 30 months, median progression-free survival (PFS) was 25 months for the total population (95% confidence interval [CI] 16- not analyzed). Patients with de novo mBC had longer median PFS than patients with recurrent disease (not reached vs. 18 months; hazard ratio 1.99; 95% CI 0.69-3.64, p<0.022). Age, hormone receptor positivity, visceral involvement, number of Cht cycles and previous adjuvant trastuzumab did not impact PFS. Most HR-positive patients (N=55, 88.7%) received maintenance ET after induction Cht. This retrospective study provides additional data on patient characteristics, treatment and outcomes of RW HER2-positive mBC patients treated with pertuzumab and trastuzumab as first-line therapy. In our institution, maintenance ET after induction Cht has become standard clinical practice.

Real world outcomes of sequential ADC therapy in metastatic breast cancer: Patients treated with sacituzumab govitecan and trastuzumab deruxtecan.

1085 Background: Sacituzumab govitecan (SG) and trastuzumab deruxtecan (TDXd) are antibody drug conjugates (ADCs) that are approved for the treatment of HER2 low metastatic breast cancer (MBC). Both carry payloads which inhibit topoisomerase 1, and it is unknown whether these ADCs retain clinical activity when used sequentially to each other. Here we present a retrospective study of patients treated with both SG and TDXd at our institution and report real world progression free survival (PFS), clinical factors associated with longer PFS, and whether ADC sequence impacts outcome. Methods: All patients with MBC treated at MSKCC who had received both SG and TDXd (in any order) were eligible for inclusion. Clinicopathological and demographic data were obtained from retrospective chart review. PFS was determined clinically and calculated using Kaplan-Meier survival analysis. Univariate and multivariate associations of survival were assessed using Cox proportional hazards models. Results: Eighty-five patients met eligibility per the criteria above: 54 with estrogen receptor positive (ER+) MBC and 31 with triple negative breast cancer (TNBC). 33 patients received SG followed by TDXd (14 ER+, 19 TNBC), and 52 received TDXd followed by SG (40 ER+, 12 TNBC). Median age at time of second ADC treatment (ADC2) was 59 among all patients, 62 among SG first, and 58 among TDXd first. This cohort was heavily pre-treated, with median 5 prior therapies at the time of first ADC (ADC1) and 7 at the time of ADC2. Both the SG first and TDXd first cohorts had median 1 line of intervening therapy between ADCs. In the SG first group, median ADC2 (TDXd) PFS was 3.5 months (95%CI 2.7-7.7), and in the TDXd first group median ADC2 (SG) was 2.8 months (95%CI 2.6-3.7). On multivariate analysis, neither ADC sequence (SG first vs. TDXd first, HR 1.30, 95%CI 0.71-2.37, p=0.4) nor ER status (TNBC vs. ER+, HR 1.21, 95%CI 0.63-2.32, p=0.6) showed statistically significant differences in ADC2 PFS between these groups. Instead, later treatment line at the time of ADC2 was significantly associated with shorter ADC2 PFS (continuous, HR 1.11, 95%CI 1.01-1.23, p=0.03). To separately evaluate differences in PFS for each ADC depending upon whether it was first or follow-up therapy, median ADC1 vs. ADC2 PFS is summarized by ADC (Table). Conclusions: In this heavily pre-treated patient cohort, the clinical activity of both SG and TDXd appear modest in the ADC2 setting. Further studies are needed to confirm these findings and to determine whether payload cross-resistance may undermine the benefit of sequential ADC therapy. [Table: see text]

A phase I/II trial of palbociclib, pembrolizumab, and endocrine therapy for patients with HR+/HER2- locally advanced or metastatic breast cancer (MBC): Clinical outcomes and stool microbial profiling.

1038 Background: Based on preclinical data highlighting synergy between CDK4/6 inhibitors and immune checkpoint inhibitors (ICIs), we conducted a phase I/II study of palbociclib, pembrolizumab, and endocrine therapy (ET) in pts with HR+/HER2- MBC. Given evidence suggesting a correlation between ICI response and stool microbiome composition in a wide array of cancers, we sought to determine if this biomarker could segregate responders in our cohort. Methods: Pts with stage IV HR+/HER2- MBC were enrolled and treated with palbociclib, pembrolizumab, and ET. Cohort 1 enrolled pts with stable disease on palbociclib + ET for at least 6 months. Cohort 2 and 3 enrolled pts in the first-line (1L) setting, with cohort 3 designed with a palbociclib + ET lead-in to evaluate the immune potentiating effect of palbociclib (not included in this report). The primary endpoint was objective response rate (ORR); secondary endpoints included progression-free survival (PFS), overall survival (OS), and toxicity. Correlative studies assessed the association between the gut microbiome and response using previously published methods (1). Results: Between March 2017 and May 2022, 40 pts were accrued, with 4, 19 and 17 pts in cohorts 1, 2 and 3, respectively. There were 39 females and 1 male, with a median age of 51 (range 39-75). The ORR in cohorts 1, 2 and 3 were 2/4 (50%), 11/19 (58%) and 13/17 (76%), respectively. Median PFS across cohorts 2 and 3 (reflecting 1L therapy) was 25 mo (95% CI 21- not reached), and at a median follow-up of 35 mo, OS was 76% (95% CI 0.60-0.96). The most common grade 3/4 adverse events across all cohorts included neutropenia (83%), leukopenia (56%), elevated alanine aminotransferase (13%), elevated aspartate aminotransferase (13%), and thrombocytopenia (10%). Gut microbial profiling (total N=24 pts; Arm 2 N=7, Arm 3 N=17) demonstrated multiple species higher in abundance in pts with a response (p &lt; 0.05), with notable species belonging to the families Lachnospiraceae, Ruminococcaceae, and Rikenellaceae. Several metabolic pathways were enriched in responders (p-value &lt; 0.05), including pathways related to fatty acid biosynthesis and the tricarboxylic acid (TCA) cycle. Conclusions: Pembrolizumab added to palbociclib + ET in the 1L setting demonstrated a higher response rate compared to palbociclib + ET alone in HR+/HER2- MBC. Specific gut profiles were associated with response, with similar taxa of bacteria associated with ICI response in other tumor types (2). Enriched metabolic pathways may generate microbiota-derived metabolites that have an immunomodulatory effect. These results suggest that the gut microbiome may be associated with response to ICI combination therapy in MBC, which warrants further evaluation. 1. Dizman et al.,Nature Med 2022. 2. Spencer et al Science 2021. Clinical trial information: NCT02778685 .

Use of liquid biomarker thymidine kinase activity (TKa) to predict outcome and progression in patients with metastatic breast cancer (MBC) in the GEICAM/2014-12 FLIPPER trial.

1028 Background: There is a need for more precise blood-based tumor biomarkers in MBC. TKa is a liquid proliferation biomarker providing prognostic, predictive and monitoring information in MBC. TKa can be measured in blood using the DiviTum TKa assay. Here we report the results of TKa in a trial of endocrine therapy (ET) fulvestrant (F) + the CDK4/6 inhibitor (CDK4/6i) Palbociclib (Pa) vs. F + Placebo (Pl), the GEICAM FLIPPER trial (NCT02690480), a multicenter, double-blind, randomized (1:1) study. F+Pa showed 1-year PFS rates of 83.5% vs. 71.9% (p=0.064) and better median (m)PFS (31.8 vs. 22.0 months, p=0.001) than F+Pl in first line treatment of HR+/HER2- MBC patients. F+Pa also significantly improved ORR and CBR. ET+CDK4/6i are currently the cornerstone of treatment for HR+/HER2- MBC. However, 10-30% of these patients display primary resistance to treatment. Early identification of patient subsets with different risk of progression during treatment with CDK4/6i may help tailor clinical management and disease monitoring. Methods: Sequential plasma was collected from 187 patients (pts) at baseline (BL) and at 12, 24, 36, 48 weeks (w) on treatment, and at progression. 910 samples were analyzed for TKa with the FDA approved and CE labelled DiviTum TKa assay (Biovica, Sweden) using DuA (DiviTum unit of Activity) as measuring unit. The cutoff for categorizing in high vs low is 250 DuA. The Kaplan-Meier method was used to estimate mPFS and mOS. Unadjusted and adjusted hazard ratio (HR) and odds ratio (OR) with 95% confidence interval (CI) were calculated with the Cox proportional hazards regression model and with logistic regression respectively, considering relevant confounders. Results: Low BL TKa predicted better PFS (30.5 months mPFS in low vs 19.8 in high, HR 1.62; 95% CI 1.11-2.35, p=0.011) and OS (HR 1.81; 95% CI 1.15-2.85, p=0.0099). Higher TKa at BL and at 12w was detected in pts that progressed before 12 months. Conversely, low BL TKa, maintained throughout week 12-48, were associated with objective response (HR 2.58; 95% CI 1.38-4.81, p=0.0029) and OS (HR 5.74; 95%CI 2.06-16, p=0.0008). At progression, pts on F+Pa tended to have higher TKa levels than F+Pl (246 vs. 138 DuA), reflecting faster growing tumors, not achieving statistical significance (p=0.0585). TKa monitoring and dynamics from BL and on treatment timepoints (week 12-48) show that the group of pts with low TK at BL that remain low during treatment is enriched with non-progressors and pts that progress after 12 months (p=0.0108). High TKa at BL predicted shorter OS in the F+Pa arm (HR 4.39; 95% CI 2.15-8.99, p&lt;0.0001). Conclusions: Measuring blood TKa levels can monitor and predict efficacy of F+/-Pa at BL and during therapy in MBC. TKa dynamics before and during therapy are associated with PFS and OS. Future studies will provide additional knowledge on the utility of TKa in MBC. Clinical trial information: NCT02690480 .

Genomic testing and uptake of alteration-targeted therapies among patients with hormone-receptor positive (HR+) metastatic breast cancer (MBC).

e13084 Background: There is no recognized standard of care treatment after progression on first-line endocrine therapy plus CDK4/6 inhibitor in HR+ / HER2 negative MBC. Alteration-targeted therapies (ATT) have the potential to delay initiation of chemotherapy with more favorable toxicity, and perhaps improved efficacy. Next-generation sequencing (NGS) of tumor tissue or circulating tumor DNA (ctDNA) can identify actionable mutations for targeted therapy. In this study, we sought to assess the results of genomic testing and uptake of ATT among patients with HR+ / HER2-negative MBC. Methods: We studied a retrospective cohort of patients with MBC who received treatment in the Koontz Center for Advanced Breast Cancer (KABCC) at St. Luke’s Cancer Institute, a community-based health system in the Kansas City metro area. The analytic cohort included 125 patients with HR+ / HER2-negative MBC who received treatment after progression on first-line therapy. Genomic testing was performed as a standard of care from ctDNA or tumor-tissue using commercially available NGS assays. Targetable alterations were defined as those with FDA-approved or routinely used off-label treatment regimens in MBC ( PIK3CA, PTEN, AKT, ESR1, ERBB2, BRCA1, BRCA2, PALB2 mutations; TMB &gt;10 or PDL1+). We identified patients who received any ATT and compared them with those who did not. Overall survival (OS) and time to initiation of chemotherapy (TTC) were compared between the two groups using Kaplan-Meier analyses and the log-rank test. Results: Ninety-nine patients (79.2%) had genomic testing and 49 (39.2%) were tested prior to second-line therapy. Of those tested, 84% had at least one targetable alteration. ESR1 mutations were most common, detected in 36% of patients, followed by PIK3CA (31.2%), PTEN (12%), BRCA1/2 (7.2%) and ERBB2 (5.6%). A total of 35 patients received ATT, and around half of those (17 patients) received ATT in the second line. Alpelisib was the most common ATT (62.9%), followed by elacestrant (20%) and neratinib (14.3%). There was no significant difference in OS or TTC between the two groups. Conclusions: Approximately 80% of patients with HR+ / HER2-negative MBC in our cohort underwent genomic testing after progression on first-line therapy, and the vast majority had at least one targetable alteration identified. However, only 35 patients received ATT with most receiving alpelisib. We observed no significant improvement in OS or TTC among those who received ATT, although the numbers were small. There have been two new targeted therapies approved in the past year and many novel agents are currently under investigation in clinical trials. Newer therapies with distinct targets, improved tolerability and efficacy have the potential to improve the uptake and clinical benefit of targeted therapy in MBC.

Efficacy of first-line dual oral pyrotinib plus capetabine therapy in HER2-positive metastatic breast cancer: A real-world retrospective study.

The combination of dual-targeted human epidermal growth factor receptor 2 (HER2) therapy and chemotherapy is the standard first-line regimen for recurrent/metastatic breast cancer (mBC). However, the toxicity of such combination therapy can lead to some patients being unable to tolerate adverse events or bear treatment costs. As a novel irreversible pan-ErbB receptor TKI (pyrotinib), can the dual oral administration of pyrotinib plus capetabine (PyroC) provide first-line survival benefits and serve as a more affordable treatment option? This real-world retrospective study included patients diagnosed with HER2-positive mBC who received PyroC as a first-line treatment at West China Hospital between May 2018 and July 2023. The survival data and toxicity profiles were reported in this study. A total of 64 patients received PyroC as first-line therapy. The median progression-free survival (PFS) was 19.6 months (95% CI 15.0-27.2), while overall survival (OS) has not yet been reached. Kaplan-Meier analysis indicated that age (≥60, p = 0.03) and metastasis sites (p = 0.004) were related to poor efficacy of PyroC, while there was no relationship between effectiveness and menstrual status, hormone receptor (HR) status or previous treatment with anti-HER2 therapy. Furthermore, the objective response rate (ORR) and disease control rate (DCR) were 79.7% and 98.4%, respectively. Of the patients, 78.1% reported treatment-related adverse events (TRAEs). The predominant adverse events were diarrhea (n = 46, 71.9%) and hand-foot syndrome (n = 10, 15.6%). The dual oral administration regimen (PyroC) has a promising ORR or PFS in HER2-positive mBC patients, with an acceptable safety profile and convenience.

LINC02535 + miR-30a-5p combination enhances proliferation and inhibits apoptosis in metastatic breast Cancer cells

Current clinical therapies for metastatic breast cancer (MBC) have limited therapeutic efficacy and induce significant systemic side effects, leading to poor patient compliance. To address this challenge, this investigation focuses on the design of LINC02535 + miR-30a-5p for treating breast cancer. In vitro cytotoxicity studies confirmed that LINC02535 + miR-30a-5p was more effective in 4 T1 cells, with reduced toxicity in NIH3T3 cells. Further verification of cellular morphology was achieved through various biochemical staining methods. Additionally, the antimetastatic attributes of LINC02535 + miR-30a-5p have been evaluated using both migration scratch and Transwell migration assays, which have collectively revealed excellent antimetastatic potential. The DNA fragmentation of the 4 T1 cells was assessed using a comet assay. LINC02535 + miR-30a-5p improved ROS levels and caused mitochondrial membrane potential alterations and DNA damage, which resulted in apoptosis. Therefore, we propose that LINC02535 + miR-30a-5p could be an alternative therapeutic strategy for breast cancer therapy.

CDK4/6 inhibitors: The Devil is in the Detail.

Update on the most recent clinical evidence on CDK4/6 inhibitors (CDK4/6i) in the treatment of hormone receptor (HR)-positive, human epidermal growth factor receptor (HER)2-negative breast cancer. Over the past decade, CDK4/6i have become part of the standard of care treatment of patients with both metastatic and high-risk early HR + /HER2- breast cancers. The three available CDK4/6i (palbociclib, ribociclib and abemaciclib) have been extensively studied in combination with endocrine therapy (ET) in metastatic breast cancer (mBC) with consistent prolongation of progression free survival; however, ribociclib has emerged as the preferred first line agent in mBC given overall survival benefit over endocrine monotherapy. In early BC, abemaciclib is the only currently approved agent while ribociclib has early positive clinical trial data. Toxicities and financial burden limit the use of CDK4/6i in all patients and resource-poor settings, and optimal timing of their use in mBC remains unclear. There is considerable evidence for the use of CDK4/6i in metastatic and early HR + /HER2- breast cancer, but knowledge gaps remain, and further research is necessary to better define their optimal use.