Advanced Metastatic Breast Cancer Research Articles

Abstract PO3-18-06: First-in-human phase 1A study of RGT-419B, a next generation CDK4 inhibitor, in patients (pts) with hormone receptor positive (HR+) HER2- advanced/metastatic breast cancer (ABC) who progressed on prior CDK4/6 inhibitors (CDK4/6i)

Abstract Introduction: RGT-419B is a novel next generation CDK inhibitor. It has high potency against CDK4 with additional activity against CDK2 and selectivity against CDK6 to overcome resistance and reduce hematologic toxicity. In addition to anti-cancer activity in preclinical breast cancer models that are resistant to approved CDK4/6 inhibitors, we report the interim data from the first-in-human, multicenter trial of RGT-419B as a single agent in post-menopausal pts with HR+ HER2- ABC. Methods: Eligible pts received ≥2 lines of treatment and progressed on endocrine therapy (ET) and at least 1 line of an FDA approved CDK4/6i. Prior treatments of fulvestrant, other targeted agents and/or chemotherapy were allowed. Dose escalation of RGT-419B as oral (PO) monotherapy was administered in continuous 28-day cycles in 4 cohorts (25, 75,150 mg QD and 150 mg BID). A standard 3+3 design was employed to determine the maximum tolerated dose (MTD)/recommended dose for expansion (RDE). The primary objective was to assess safety and tolerability. The secondary objectives included pharmacokinetic (PK) assessment and exploratory efficacy. Results: At time of abstract submission, 12 eligible post-menopausal pts with HR+/HER2- ABC received RGT-419B. The median age was 64.8y (range 50-80y). All had prior palbociclib + ET (2 pts had abemaciclib or ribociclib after palbociclib); a majority received fulvestrant (67%) and prior chemotherapy (50%). Across the 4 cohorts (12 pts), the most observed treatment-emergent adverse events (TEAEs; all causality) with RGT-419B were nausea, reduced white blood cell counts (neutrophils and/or lymphocytes) and diarrhea. At data cutoff on June 30th 2023, there have been no CTCAE Grade 3 or higher treatment related AE (TRAEs). No ocular toxicity has been observed. No pts have discontinued treatment due to RGT-419B toxicity. Preliminary PK analyses for RGT-419B showed a dose-dependent increase of exposure at steady state with long half-life. Tumor assessments (RECIST v1.1) of pts in the first 3 cohorts treated with RGT-419B monotherapy (25-150 mg QD) showed partial responses in 2 pts (7 pts with measurable disease), 28.6% partial response (PR) (RECIST v. 1.1) and clinical benefit rate (CBR) 44%. Updated safety, PK and efficacy data will be presented. Conclusions: RGT-419B, with potent selective CDK4 activity, CDK2 activity and CDK6 selectivity, demonstrated a favorable safety and PK profile in an ongoing phase I study, with no grade 3 or higher TRAEs observed thus far. RGT-419B administered as once daily monotherapy also demonstrated preliminary evidence of efficacy as well. Dose expansions of RGT-419B as a single agent and in combination with ET in pts with HR+/HER2- ABC following prior CDK4/6i progression are planned. Citation Format: Seth Wander, Dave Valacer, Richard Zuniga, Heather Yeckes-Rodin, Christopher Perkins, Lisa Ge, Lili Yao, Jing Lin, Dawn Begley, Feifei Sun, Andie Zheng, Jing Han, Zhi (Julie) Xie, Aditya Bardia, Kevin Kalinsky. First-in-human phase 1A study of RGT-419B, a next generation CDK4 inhibitor, in patients (pts) with hormone receptor positive (HR+) HER2- advanced/metastatic breast cancer (ABC) who progressed on prior CDK4/6 inhibitors (CDK4/6i) [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-18-06.

Abstract PO4-04-12: A Phase 1b/2 study of palazestrant (OP-1250) in combination with ribociclib or alpelisib in patients with estrogen receptor-positive, human epidermal growth factor receptor 2-negative, advanced and/or metastatic breast cancer

Abstract Background: Endocrine therapy (ET) when administered with cyclin-dependent kinase 4/6 (CDK4/6) inhibitors has improved outcomes in patients (pts) with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer (BC) or metastatic breast cancer (MBC) and is the current standard of care for first-line treatment. Addition of the PIK3 inhibitor alpelisib to ET significantly improved progression-free survival in pts with PIK3CA-mutated, ER-positive, HER2-negative MBC, and alpelisib + fulvestrant is the standard of care for second or later-line treatment. Most pts will acquire resistance to ET, with mutations in ESR1 constituting the most common mechanism of resistance. Palazestrant (OP-1250) is a small molecule oral complete ER antagonist (CERAN) and selective ER degrader (SERD) that binds the ligand binding domain of ER and completely blocks ER-driven transcriptional activity in both wild-type (ESR1-wt) and mutant (ESR1-mut) forms of ER. In preclinical studies, palazestrant in combination with ribociclib demonstrated activity in both ESR1-wt and ESR1-mut xenograft models and showed efficacy in brain metastasis xenograft models. In a Phase 1/2 monotherapy study in pts with ER-positive, HER2-negative MBC, palazestrant was well tolerated with demonstrated antitumor efficacy and favorable pharmacokinetics (PK) supporting once a day (qd) dosing at the recommended Phase 2 dose (RP2D) of 120 mg. The aim of this study is to evaluate the safety, PK, and antitumor activity of palazestrant + ribociclib or alpelisib in pts with ER-positive, HER2-negative advanced BC or MBC. Methods: Eligible pts have evaluable ER-positive, HER2-negative advanced BC or MBC; ≤2 prior ETs (prior CDK4/6 inhibitors allowed); and ≤1 prior line of chemotherapy. In the alpelisib arm, pts must have a PIK3CA mutation in the tumor or ctDNA. Patients are administered oral palazestrant at escalating doses of 30, 60, and 120 mg qd in combination with the approved dose of oral ribociclib (600 mg qd; days 1–21 of 28-day cycle) or approved dose of oral alpelisib (300 mg qd) in a 3+3 design to identify the RP2D. The dose-expansion part will assess additional safety and PK parameters and the antitumor activity of palazestrant in combination with ribociclib or alpelisib (NCT05508906). Results: As of June 15, 2023, 10 pts have received 30 mg and 60 mg doses of palazestrant in combination with ribociclib (n=6) or alpelisib (n=4). No dose-limiting toxicities have been observed. After administration in the first two combination dose levels of 30 and 60 mg, palazestrant exposure was consistent with monotherapy administration; exposure data show no drug–drug interactions (DDI) when compared to published exposure parameters. Most reported treatment-emergent adverse events (TEAEs) were grade 1 or 2 and consistent with the known safety profiles of all 3 drugs. In the ribociclib arm, the TEAEs occurring in ≥2 pts included grade 1 nausea (n=4), grade 1 constipation (n=2), and neutropenia (grade 2, n=1; grade 3, n=3). For the 3 pts in the 30 mg palazestrant + alpelisib cohort, the only TEAE occurring in ≥2 pts was grade 1 diarrhea. One pt had grade 1 hyperglycemia. Conclusions: In this ongoing study, palazestrant in combination with ribociclib or alpelisib was well tolerated, and enrollment to the palazestrant 120 mg dose with ribociclib or alpelisib is ongoing. No new safety signals were observed for the 3 drugs, and no clinically significant DDIs were observed between palazestrant and ribociclib or alpelisib at the doses evaluated. Exposure of each drug was consistent with observed monotherapy exposure levels. Updated data will be presented. Citation Format: Virginia Borges, Carlos Alemany, Nancy Lin, Sara Nunnery, Cynthia Ma, Margaret Tonda, Morena Shaw, Arlene Chan. A Phase 1b/2 study of palazestrant (OP-1250) in combination with ribociclib or alpelisib in patients with estrogen receptor-positive, human epidermal growth factor receptor 2-negative, advanced and/or metastatic breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-04-12.

Abstract PO3-18-09: OPERA-01: A randomized, open-label, phase 3, study of palazestrant (OP-1250) vs standard-of-care treatment for ER+, HER2- advanced or metastatic breast cancer after endocrine and CDK4/6 inhibitor therapy

Abstract Background: In estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC), adding a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor to endocrine therapy (ET) has improved outcomes and is the current standard-of-care treatment in the first-line setting. However, resistance to first-line treatment develops in most patients (pts), which is often attributed to acquired mutations in ESR1. Limited data exist for ET-based treatment options after progression on prior ET and CDK4/6 inhibitors, and most pts will transition to chemotherapy for further treatment. Therefore, there is a significant unmet need for more effective ET in pts with ER-positive, HER2-negative MBC to improve outcomes and delay time to chemotherapy. Palazestrant (OP-1250) is a small molecule oral complete ER antagonist (CERAN) and selective ER degrader (SERD) that binds the ligand binding domain of ER and completely blocks ER-driven transcriptional activity in both wild-type (ESR1-wt) and mutant (ESR1-mut) forms of ER. In preclinical studies, palazestrant demonstrated better tumor shrinkage in ESR1-wt and ESR1-mut models when compared to fulvestrant; it also showed efficacy in brain metastasis models. In a phase 1/2 monotherapy study in pts with heavily pretreated ER-positive, HER2-negative advanced breast cancer (BC) or MBC (NCT04505826), palazestrant showed a tolerable safety profile, promising antitumor efficacy, and favorable pharmacokinetics (PK) supporting once a day (qd) dosing. The recommended Phase 2 dose of palazestrant is 120 mg qd. Methods: The OPERA-01 trial is an international, multicenter, randomized, open-label, phase 3 clinical trial comparing the efficacy and safety of palazestrant as a single agent to standard-of-care ET (fulvestrant, anastrozole, letrozole, or exemestane) in pts with ER-positive, HER2-negative advanced BC or MBC that has relapsed or progressed on 1 or 2 prior lines of ET for MBC, which includes a CDK4/6 inhibitor. Eligible pts are women (pre- or post-menopausal) or men who have a confirmed diagnosis of ER-positive, HER2-negative locally advanced evaluable BC or MBC not amenable to curative therapy. ER and HER2 status are determined according to the American Society of Clinical Oncology/College of American Pathologists guidelines. Patients must have Eastern Cooperative Oncology Group performance status 0 or 1. Prior treatments must include 1 or 2 prior lines of ET as monotherapy or in combination with a CDK4/6 inhibitor for MBC; must have received CDK4/6 inhibitor in combination with ET and have disease progression during or within 28 days of completion of each line of prior treatment for MBC; most recent ET given for ≥6 months. Prior chemotherapy in the metastatic setting is not permitted. Patients (N∼500) are randomized to palazestrant or standard-of-care ET monotherapy, and are stratified by ESR1 mutation status, prior lines of ET for advanced disease (1 vs 2 lines), and presence or absence of visceral disease. The primary endpoint of progression-free survival will be assessed by blinded independent central review in pts with and without ESR1 mutations in the intent-to-treat population. Secondary endpoints include overall survival, antitumor activity (objective response rate, clinical benefit rate, and duration of response), safety, patient-reported outcomes, and PK in pts with and without ESR1 mutations. The study is planned to be conducted globally. Citation Format: Arlene Chan, Jane Meisel, Komal Jhaveri, Joo Hyuk Sohn, Meritxell Bellet- Ezquerra, Jason Schroeder, Mark Shilkrut, Barbara Pistilli. OPERA-01: A randomized, open-label, phase 3, study of palazestrant (OP-1250) vs standard-of-care treatment for ER+, HER2- advanced or metastatic breast cancer after endocrine and CDK4/6 inhibitor therapy [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-18-09.

Abstract PO1-06-01: Clinical Efficacy of Tumor Organoid-Guided Cancer Therapy for Locally Advanced Unresectable or Metastatic Breast Cancer

Abstract Purpose: Patient-derived organoids (PDOs) may facilitate treatment selection, but the feasibility of using breast cancer PDOs to guide personalized treatment in clinical practice has not been fully investigated. This study aimed to assess the clinical efficacy of treatment guided by PDO drug sensitivity tests (OGT) versus treatment of physician’s choice (TPC) in patients with locally advanced unresectable or metastatic breast cancer (MBC) and to explore the potential of PDOs to reveal mechanisms underlying treatment resistance. Methods: Patients diagnosed with MBC were recruited between January 2020 and August 2022. PDOs were established from biopsies specimens or malignant effusion samples. The efficacy of customized drug panels was determined by measuring cell mortality after drug exposure. Patients receiving OGT were matched 1:2 by nearest neighbor propensity scores with patients receiving TPC. The primary clinical outcome was progression-free survival. Secondary outcomes included objective response rate and disease control rate. Targeted gene sequencing and pathway enrichment analysis were performed. Results: 46 PDOs (46 of 51, 90.2%) were generated from 45 MBC patients. PDO drug screening showed an accuracy of 81.1% (95% CI 67.6%-91.9%) in predicting patients' clinical responses. 36 OGT patients were matched to 69 TPC patients. OGT was associated with prolonged median progression-free survival (11.0 months vs 5.0 months; unadjusted hazard ratio 0.53 [95% CI 0.33-0.85]; P=0.01) and improved disease control (88.9% vs 63.8%; unadjusted odd ratio 4.26 [1.44-18.62]) compared with TPC. The objective response rate of both groups was similar. Pathway enrichment analysis uncovered differentially modulated pathways implicated in DNA repair and transcriptional regulation in patients less sensitive to capecitabine/gemcitabine, and pathways associated with cell cycle regulation in patients less sensitive to palbociclib. Conclusions: MBC patients treated with OGT were associated with superior progression-free survival and disease control compared with TPC. PDO-based functional precision medicine is a feasible strategy for treatment optimization and customization in MBC and may enhance our understanding of therapeutic resistance. Citation Format: Ying-Yi Lin, Hong-Fei Gao, Hong Li, Bo-Lei Du, Min-Yi Cheng, Jia-Chen Zou, Xing-xing Zheng, Teng Zhu, Ting-Ting Li, Sheng Li, Kun Wang. Clinical Efficacy of Tumor Organoid-Guided Cancer Therapy for Locally Advanced Unresectable or Metastatic Breast Cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-06-01.

Abstract 2283: A targeted mutation calling workflow - end to end - from FASTQ to clinical report for single cells

Abstract Molecular profiling of rare cancer cells derived from liquid biopsy holds promise to monitor systemic cancer progression and guide personalized therapy interventions. However, this necessitates reliable and comprehensive profiling of samples at the single cell level and requires whole genome amplification (WGA), which adds amplification errors and bias to common sequencing errors. Therefore, we established a single-cell mutation calling workflow that can identify clinically actionable somatic mutations in rare single cell DNA with high sensitivity and accuracy. Our workflow is an end-to-end solution which can take FASTQ reads from any Panel Sequencing (PanelSeq) data and gives out single nucleotide variations (SNVs), insertion-deletions (InDels), and copy number variations (CNVs) in single cells alongside with mutation specific information from ClinVar, OncoKB, pathogenicity scores, conservations scores as well as known association to drug response and resistance. We incorporated a Bayesian Neural Network (NN) based Classifier algorithm that assigns a single statistical confidence score to the mutations, enabling prioritization of the mutations in a robust manner. On the training dataset including MDA-MB-453, BT474, BT549 and ZR-75.1 cell lines, the classifier achieved 91% sensitivity and 96% specificity (AUC=0.98), while on the independent test collective including HCC1395/HCC1395BL cell lines it achieved 84% sensitivity and 96% specificity (AUC=0.90). We applied the workflow to patient samples suffering from advanced metastatic Triple Negative Breast Cancer (TNBC) assayed with in-house single-cell Integrated Mutation Profiling of Actionable Cancer Targets (scIMPACT) and single-cell Whole Exome Sequencing (scWES). Using our method, we detected clinically actionable SNVs with pathogenic relevance in primary tumor, metastatic specimens, circulating tumor cells (CTCs) from blood and disseminated cancer cells (DCC) from pleural effusions, as well as the matched CTC-derived in vivo models (CDX). Notably, functional in vitro drug screens performed on CDX models uncovered susceptibility to approved drug treatments conferred by mutations detected in the samples. In summary, we introduce a novel mutation calling workflow facilitating detection of SNVs, Indels and CNVs in rare single cells with high sensitivity and precision. Confident scores assigned by the NN classifier enables identification of functionally actionable mutations. The workflow was executed in GDPR compliant fashion and follows all data protection standards imposed by the European laws. Accordingly, the method is well suited for molecular profiling, therapeutic target selection and longitudinal monitoring of liquid biopsy specimens in diagnostic environments. Citation Format: Adithi Ravikumar Varadarajan, Thomas Ragg, Jonas Grote, Vadim Dechand, Steffi Treitschke, Clara Chaiban, Christoph Klein, Zbigniew Czyz, Jens Warfsmann. A targeted mutation calling workflow - end to end - from FASTQ to clinical report for single cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2283.

Application of fluorocarbon nanoparticles of 131I-fulvestrant as a targeted radiation drug for endocrine therapy on human breast cancer

BackgroundBreast cancer is the most prevalent malignant tumor among women, with hormone receptor-positive cases constituting 70%. Fulvestrant, an antagonist for these receptors, is utilized for advanced metastatic hormone receptor-positive breast cancer. Yet, its inhibitory effect on tumor cells is not strong, and it lacks direct cytotoxicity. Consequently, there's a significant challenge in preventing recurrence and metastasis once cancer cells develop resistance to fulvestrant.MethodTo address these challenges, we engineered tumor-targeting nanoparticles termed 131I-fulvestrant-ALA-PFP-FA-NPs. This involved labeling fulvestrant with 131I to create 131I-fulvestrant. Subsequently, we incorporated the 131I-fulvestrant and 5-aminolevulinic acid (ALA) into fluorocarbon nanoparticles with folate as the targeting agent. This design facilitates a tri-modal therapeutic approach—endocrine therapy, radiotherapy, and PDT for estrogen receptor-positive breast cancer.ResultsOur in vivo and in vitro tests showed that the drug-laden nanoparticles effectively zeroed in on tumors. This targeting efficiency was corroborated using SPECT-CT imaging, confocal microscopy, and small animal fluorescence imaging. The 131I-fulvestrant-ALA-PFP-FA-NPs maintained stability and showcased potent antitumor capabilities due to the synergism of endocrine therapy, radiotherapy, and CR-PDT. Throughout the treatment duration, we detected no notable irregularities in hematological, biochemical, or histological evaluations.ConclusionWe've pioneered a nanoparticle system loaded with radioactive isotope 131I, endocrine therapeutic agents, and a photosensitizer precursor. This system offers a combined modality of radiotherapy, endocrine treatment, and PDT for breast cancer.Graphical

Lacked of Breast Cancer Awareness of Indonesian Rural Women: A Descriptive Study to Adult Women in District Pangandaran, Indonesia

Breast cancer remains a significant global health challenge, particularly in low and middle-income countries like Indonesia. Patients with advanced metastatic breast cancer have a dismal prognosis. A cancer promotion program’s failure can be attributed to low awareness of breast cancer. This descriptive study aimed to evaluate breast cancer awareness among adult women in District Pangandaran, Indonesia. Data was gathered in July 2018 from 189 individuals using a verified Breast Cancer Awareness Measure instrument developed by Cancer Research UK. Results revealed a concerning lack of awareness among participants regarding various breast cancer risk factors, symptoms, and screening practices. Additionally, reluctance to seek medical help due to fear of diagnosis was observed, particularly among housewives without health insurance. These findings highlight the urgent need for comprehensive health programs to enhance breast cancer awareness and promote early detection strategies tailored to the Indonesian population, especially in rural areas. Healthcare providers and public health workers play a vital role in this effort, along with implementing innovative health promotion policies by the government to improve cancer prevention programs.

PIK3CA Mutational Profiling in a Patient Cohort with HR+/HER2- Advanced Metastatic Breast Cancer at a Tertiary Cancer Center

PIK3CA Mutational Profiling in a Patient Cohort with HR+/HER2- Advanced Metastatic Breast Cancer at a Tertiary Cancer Center

Prognostic value and distribution pattern of tumor infiltrating lymphocytes and their subsets in distant metastases of advanced breast cancer

BackgroundThere are significant correlations between the levels of tumor infiltrating lymphocytes (TILs) and the prognosis of primary breast cancer. While little is known about immunological mechanisms in the distant metastasis of advanced breast cancer. Patients and MethodsA total of 106 patients with advanced metastatic breast cancer were enrolled in this study between 2016 and 2022. Hematoxylin and eosin staining and immunohistochemistry were used to assess the densities of stromal TILs (sTILs), intratumoral TILs (iTILs) and invasive marginal TILs (imTILs) and CD4+, CD8+, CD20+, FOXP3+ TILs in the primary tumor and metastasis (bone, lung, liver, and distant lymph node) of advanced breast cancer. ResultsHigher levels of sTILs at metastatic sites were associated with better progression-free survival (PFS), postmetastasis survival (PMS) and overall survival (OS) (p = .026, .001 and .005, respectively). The levels of iTILs were significantly lower than those of sTILs and imTILs in both primary tumor (p< .001, both) and metastasis (p< .001, both). The level of CD4+ T cells was higher than those of CD8+ T cells and CD20+ B cells in both primary tumor (p < .001) and metastasis (p < .001). The levels of sTILs (p=0. 001) and imTILs (p< .001) in the primary tumor were generally higher than those in the metastasis. ConclusionThe levels of TILs and their subsets can predict the survival and prognosis of patients with advanced breast cancer. The distributions of TILs and their subsets are similar between the primary tumor and metastasis. The metastases have a lower degree of lymphocytes infiltration than its corresponding primary tumor.

Revolutionizing Breast Cancer Patient Management: Analysis of R-SH Quantification Unveils Redox Imbalance Signatures in Advanced Metastatic Breast Cancer

Revolutionizing Breast Cancer Patient Management: Analysis of R-SH Quantification Unveils Redox Imbalance Signatures in Advanced Metastatic Breast Cancer

Evaluation of the IMPACT of a decision-support platform (Trapelo) on testing patterns for patients with advanced solid tumors.

513 Background: Given the evolving precision oncology landscape, it is challenging for oncologists to stay abreast of the latest biomarker testing guidelines. Texas Oncology (TxO), a network of community oncology providers, is evaluating Trapelo, a decision-support platform that assists in the ordering of appropriate biomarker tests. The objective of this study was to assess whether implementation of Trapelo’s testing pathways improves the ordering of timely and comprehensive biomarker testing (TCBT) among patients with advanced cancer. Methods: We conducted a retrospective analysis of patients with advanced non-small cell lung (NSCLC), metastatic breast (BC), or metastatic colorectal (CRC) cancer treated at TxO between July 24, 2018, and July 24, 2021, and had at least one oncology biomarker test ordered. The ‘Intervention’ group consisted of patients diagnosed after their physician’s onboarding to Trapelo; the ‘Control’ group consisted of patients diagnosed before onboarding. We also analyzed a subset of the intervention group: patients with biomarker tests actually ordered through Trapelo (Intervention - Trapelo.) Our primary endpoint, TCBT, was defined as the ordering of tests for all actionable biomarkers (i.e., with FDA approved first-line treatment) within 60 days following an advanced diagnosis. Because Trapelo implementation occurred over time, we used Two-Way Fixed Effects regression with fixed effects for time period and physician to assess the impact of the Intervention on TCBT. Results: In descriptive analysis, the rates of TCBT in the NSCLC cohort were 26, 28%, and 37% in the Control (n = 1023), Intervention (n = 554), and Intervention-Trapelo (n = 315) groups, respectively. In the CRC and BC cohorts, the rates were 32%, 40%, 55%, and 66%, 55%, and 45%, respectively. In the regression analysis, Intervention was associated with increases in TCBT rates of 7.5 ( p = 0.4) and 6.5 ( p = 0.4) percentage points in the CRC and NSCLC cohorts, respectively. The lack of statistical significance could be attributable to small sample sizes and clustered data by physicians. No differences were observed in the BC cohort. Conclusions: While trends observed in our study indicate that implementation of a decision support tool can improve rates of TCBT in a community oncology setting, studies with larger sample sizes are needed to assess the statistical significance of these findings. Despite these potential improvements, overall rates of TCBT, a critical aspect of optimal treatment in oncology, remained low. Further, over 43% of the NSCLC patients in the Intervention group did not have their orders placed through Trapelo, indicating an opportunity for improving post-onboarding adoption of Trapelo. Future analyses will investigate the impact of Trapelo utilization (as opposed to implementation/onboarding) on the receipt of TCBT.

Efficacy of anlotinib in Chinese patients with metastatic breast cancer: A retrospective observational study.

Anlotinib, a multitarget tyrosine kinase inhibitor, can inhibit tumour angiogenesis proliferation, metastasis, promote vascular normalization, increase T cell and NK cell activity and infiltration, remodel tumour microenvironment and synergistic immune enhancement. Our study aimes to evaluate the efficacy of anlotinib in the treatment of advanced metastatic breast cancer (MBC) after multiple lines of therapy. Patients included were treated with anlotinib for advanced MBC in the Affiliated Cancer Hospital of Zhengzhou University from 1 January 2019 to 30 June 2023. The objective remission rate, disease-free progression survival and adverse reactions were analysed. We compared and analysed the efficacy of anlotinib in the treatment of advanced metastatic breast cancer, which showed that ORR was 23.6% and DCR was 69.1%. The DCR of monotherapy was 66.7% and that of combination therapy was 69.6% in MBC patients. The combination therapy, combined with chemotherapy had the best effect (79.3%), combined with immunotherapy came second. In addition, the DCR (88.9%) was higher in MBC patients having received prior antiangiogenic therapy. According to the Kaplan-Meier (K-M) survival estimate analysis, the mPFS was 4.17 months (95% CI, 1.758-6.582 months) in Her-2 positive MBC patients, and 7.83 months (95% CI, 2.416-9.104) in Her-2 negative MBC patients. The mPFS was 5.76 months (95% CI, 3.231-8.298 m) in HR positive MBC patients, 7.83 months (95% CI, 3.182-12.478 m) in TNBC patients. Fatigue (20.0%), hypertension (21.8%) and liver dysfunction (18.2%) were common adverse reactions, followed by bone marrow suppression (16.4%), anorexia (14.5%), hypothyroidism (14.5%) and diarrhoea (14.5%). Altogether, Anlotinib monotherapy or combination therapy provides a viable third (or above)-line therapeutic strategy in patients with metastatic breast cancer. The adverse reactions of anlotinib are well tolerated and controllable.

Assessment and management of upper limb lymphoedema in advanced disease: a case study.

Lymphoedema is thought to affect around 200 000 people in the UK (NHS England, 2023). Secondary lymphoedema is a relatively common complication of cancer and cancer treatment, and in advanced disease it may present a challenging issue for community nursing staff caring for patients approaching the end of their lives. In this article, a case study considers the assessment and treatment of upper limb lymphoedema in a patient with advanced metastatic breast cancer. Management of this complex and distressing condition requires holistic assessment and collaborative care planning with the patient and their wider care team, including onward referral to specialist lymphoedema and palliative care services. The case study considers the typical presentation of lymphoedema in an upper limb, exclusion of reversible causes for oedema, awareness of palliative care emergencies such as superior vena cava obstruction, and the provision of supportive therapeutic interventions in context of the patient's expressed wishes for her ongoing care.

483P Prognostic value of androgen receptor expression in patients with advanced triple-negative metastatic breast cancer treated with sacituzumab govitecan: A French multicentre retrospective study

483P Prognostic value of androgen receptor expression in patients with advanced triple-negative metastatic breast cancer treated with sacituzumab govitecan: A French multicentre retrospective study

Serine protease inhibitors decrease metastasis in prostate, breast and ovarian cancers.

Targeted therapies for prostate, breast and ovarian cancers are based on their activity against primary tumors rather than their anti-metastatic activity. Consequently, there is an urgent need for new agents targeting the metastatic process. Emerging evidence correlates in vitro and in vivo cancer invasion and metastasis with increased activity of the proteases mesotrypsin (prostate and breast cancer) and kallikrein 6 (KLK6; ovarian cancer). Thus, mesotrypsin and KLK6 are attractive putative targets for therapeutic intervention. As potential therapeutics for advanced metastatic prostate, breast and ovarian cancers, we report novel mesotrypsin- and KLK6-based therapies, based on our previously developed mutants of the human amyloid β-protein precursor Kunitz protease inhibitor domain (APPI). These mutants, designated APPI-3M (prostate and breast cancer) and APPI-4M (ovarian cancer), demonstrated significant accumulation in tumors and therapeutic efficacy in orthotopic preclinical models, with the advantages of long retention times in vivo, high affinity and favorable pharmacokinetic properties. The applicability of the APPIs, as a novel therapy and for imaging purposes, is supported by their good safety profile and their controlled and scalable manufacturability in bioreactors.

Atezolizumab in the treatment of patients with breast cancer

Immunotherapy is a modern method of treatment which is being tested in breast cancer patients. The first approved drug in this group was atezolizumab introduced for the treatment of patients with locally advanced and inoperable or metastatic triple-negative breast cancer (TNBC) with expression of programmed death receptor type 1 (PD-L1) on immunologic cells (IC) of ≥1%, who had not received prior chemotherapy for advanced disease. The results of the registration study IMpassion130 indicated that atezolizumab improved patient outcomes when used in combination with nab-paclitaxel. This article summarizes the most important analyzes of that study. The necessity to use the validated VENTANA SP142 assay to assess PD-L1 expression, which is necessary for the qualification of patients for this therapy, was emphasized. Additionally, the available data on the first results of the studies in patients with early TNBC as well as with human epidermal receptor type 2 (HER2)-positive and estrogen receptor (ER)-positive HER2-negative cancers treated with atezolizumab are discussed.

Vinorelbine-related tetraplegia due to severe peripheral neuropathy.

Vinorelbine, a semi-synthetic vinca alkaloid with anticancer activity by binding to tubulin, has shown to be successful in the treatment of cancer types including advanced non-small cell lung cancer, uterine cancer, and metastatic breast cancer. Myelosuppression, hematological effects, nausea, vomiting, exhaustion, and neuropathy are some of the most typical side effects of vinorelbine. We discuss the unusual presentation of vinorelbine-induced tetraplegia in a breast cancer patient. A 66-year-old patient with breast cancer, who was followed up with adjuvant aromatase inhibitor therapy after mastectomy, presented with lung and bone metastases. She progressed in the follow-ups after receiving platinum and taxane chemotherapy, vinorelbine treatment was then started. The patient complained of weakness, weariness, and trouble walking after receiving a total dose of 180 mg. Tetraplegia was found after a neurological assessment. It was thought that vinorelbine was responsible for the recent acute weakness. The patient's vinorelbine treatment was stopped. During follow-up, upper extremity paresis regressed, while lower extremities muscle strength remained unchanged. Vinorelbine, frequently used in oncology practice, causes some side effects. Although very rare in the literature, in this case severe peripheral neuropathy has been reported in the follow-up of post-vinorelbine quadriparesis.

Abstract 37: Exploring the Impact of Metastatic Breast Cancer Support Group in Nigeria

Abstract Purpose: Over 70% of breast cancer patients in Nigeria present metastatic/advanced breast cancer (MBC). An estimated 90% of breast cancer deaths are a result of metastatic disease, either at diagnosis or recurrence. MBC is associated with a severe burden to the patient, family, healthcare delivery system and society at large. Women living with MBC face many challenges ranging from poor access to MBC information, untreated pain, frequent breakdown of radiotherapy machines and absence of peer support. Methods: In this research, we set up the first metastatic breast cancer support group in Abuja. The group meet once every month on a face-to-face basis and also uses WhatsApp group for regular meaningful engagement. We explored the impact of the group on the patient’s quality of life (QoL) using a focused group discussion (FGD). Eighteen (18) patients participated in the two sessions of FGD. We also conducted a follow-up semi-structured interview with 8 MBC patients. Results: Many of the patients report that the support group provides a culture of love and strength over their death anxiety, especially meeting other patients who have lived with MBC longer. They also report having found peer support on the online WhatsApp group. Citation Format: Runcie C.W. Chidebe, Mary-Gloria A. Orji, Theodora Zitta-Nwosu, Khadijat Banwo-Fatai, Agha A. Agha, Darlingtina K. Esiaka, Tochukwu C. Orjiakor. Exploring the Impact of Metastatic Breast Cancer Support Group in Nigeria [abstract]. In: Proceedings of the 11th Annual Symposium on Global Cancer Research; Closing the Research-to-Implementation Gap; 2023 Apr 4-6. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(6_Suppl):Abstract nr 37.

Drug-drug interaction potentials of tucatinib inhibition of human UDP-glucuronosyltransferases

Tucatinib is known as a tyrosine kinase inhibitor (TKI), which has been commonly approved for the treatment of adult patients with advanced unresectable or metastatic HER2-positive breast cancer. However, there haven't been systematic study about the inhibition of tucatinib on UDP-Glucuronosyltransferases (UGTs) and the potential risk of drug-drug interactions (DDIs). In present study, we aimed to systematically investigate the inhibition of tucatinib on recombinant human UGTs and pooled human liver microsomes (HLMs), and to quantitatively evaluate its potential risk of DDIs by in vitro-in vivo extrapolation (IVIVE). Our data indicated that tucatinib exhibited extensive inhibition on recombinant UGTs. Tucatinib was a weak inhibitor of UGT1A4, 2B4 and 2B7; tucatinib possessed a strong inhibitory effect on UGT1A1, UGT1A3, UGT1A6, UGT1A7, UGT1A8, UGT1A9, UGT1A10, UGT2B15 and UGT2B17, with IC50 values of 0.53 μM–15.50 μM. Especially, it also potently inhibited estradiol and SN-38 glucuronidation in HLMs with IC50 values of 46.83 μM and 1.33 μM. The quantitative prediction of DDIs risk indicated that the co-administration of tucatinib with drugs mainly metabolized by hepatic or intestinal UGTs (UGT1A1, UGT1A3, UGT1A6, UGT1A7, UGT1A8, UGT1A9, UGT1A10, UGT2B15 and UGT2B17) might result in potential DDIs risk through inhibition of glucuronidation. More attention should be paid to the influence of tucatinib on UGTs in liver and intestine to avoid unnecessary clinical DDIs risk.

Platelet count, platelet lymphocyte ratio, and Ki67 as a predictive factor of neoadjuvant chemotherapy response in locally advanced breast cancer

Link of Video Abstract: https://youtu.be/CjzggoIFnTU Background: Locally advanced breast cancer (LABC) is a term that refers to advanced non metastatic stage breast cancer. Neoadjuvant chemotherapy is one of the therapies given to patients with LABC. Many factors can affect the chemotherapy response, platelets produce growth factors, and cytokines promote angiogenesis and tumor growth. Inflammatory biomarkers such as platelet lymphocyte ratio (PLR) may indicate tumor progressiveness. The Ki67 proliferation index is a marker of the aggressiveness or growth of tumor cells. This study aimed to determine the correlation of platelet count, platelet lymphocyte ratio and Ki67 proliferation index before chemotherapy with neoadjuvant chemotherapy response. Method: This research used the cohort retrospective design method. A sample of 155 patients was selected using a simple random sampling technique. The inclusion criteria of this research are having complete data about pre-treatment platelet, lymphocyte platelet ratio, Ki67 and the neoadjuvant chemotherapy response result assessed by the oncologist that is written in the medical record. Patient data from other types of cancer, chronic, systemic or autoimmune diseases are excluded from this research. The data of each variable was analyzed with the Spearman correlation test. Result: There was no correlation between platelet count and neoadjuvant chemotherapy response (p=0.301). There was a negative correlation between the platelet lymphocyte ratio (p=0.026) and the Ki67 index (p=0.040) with neoadjuvant chemotherapy response. Conclusion: Based on this study, it can be concluded that platelet count is not significant in relation to chemotherapy responses. The higher the platelet lymphocyte ratio and the proliferation index of Ki67, the lower the response to neoadjuvant chemotherapy.