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Breast Cancer Research : BCR May 2024
PubMed: 38790033
DOI: 10.1186/s13058-024-01833-6 -
BMC Cancer May 2024HER2-positive, estrogen receptor-positive breast cancer (HER2+, ER+ BC) is a distinct disease subtype associated with inferior response to chemotherapy plus... (Randomized Controlled Trial)
Randomized Controlled Trial
heredERA Breast Cancer: a phase III, randomized, open-label study evaluating the efficacy and safety of giredestrant plus the fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection in patients with previously untreated HER2-positive, estrogen receptor-positive locally...
BACKGROUND
HER2-positive, estrogen receptor-positive breast cancer (HER2+, ER+ BC) is a distinct disease subtype associated with inferior response to chemotherapy plus HER2-targeted therapy compared with HER2+, ER-negative BC. Bi-directional crosstalk leads to cooperation of the HER2 and ER pathways that may drive treatment resistance; thus, simultaneous co-targeting may optimize treatment impact and survival outcomes in patients with HER2+, ER+ BC. First-line (1L) treatment for patients with HER2+ metastatic BC (mBC) is pertuzumab, trastuzumab, and taxane chemotherapy. In clinical practice, dual HER2 blockade plus a fixed number of chemotherapy cycles are given as induction therapy to maximize tumor response, with subsequent HER2-targeted maintenance treatment given as a more tolerable regimen for long-term disease control. For patients whose tumors co-express ER, maintenance endocrine therapy (ET) can be added, but uptake varies due to lack of data from randomized clinical trials investigating the superiority of maintenance ET plus dual HER2 blockade versus dual HER2 blockade alone. Giredestrant, a novel oral selective ER antagonist and degrader, shows promising clinical activity and manageable safety across phase I-II trials of patients with ER+, HER2-negative BC, with therapeutic potential in those with HER2 co-expression.
METHODS
This phase III, randomized, open-label, two-arm study aims to recruit 812 patients with HER2+, ER+ locally advanced (LA)/mBC into the induction phase (fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection [PH FDC SC] plus a taxane) to enable 730 patients to be randomized 1:1 to the maintenance phase (giredestrant plus PH FDC SC or PH FDC SC [plus optional ET]), stratified by disease site (visceral versus non-visceral), type of LA/metastatic presentation (de novo versus recurrent), best overall response to induction therapy (partial/complete response versus stable disease), and intent to give ET (yes versus no). The primary endpoint is investigator-assessed progression-free survival. Secondary endpoints include overall survival, objective response rate, clinical benefit rate, duration of response, safety, and patient-reported outcomes.
DISCUSSION
heredERA BC will address whether giredestrant plus dual HER2 blockade is superior to dual HER2 blockade alone, to inform the use of this combination in clinical practice for maintenance 1L treatment of patients with HER2+, ER+ LA/mBC.
TRIAL REGISTRATION
ClinicalTrials.gov, NCT05296798; registered on March 25, 2022. Protocol version 3.0 (November 18, 2022).
SPONSOR
F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124 4070, Basel, Switzerland.
Topics: Humans; Female; Breast Neoplasms; Receptor, ErbB-2; Antineoplastic Combined Chemotherapy Protocols; Trastuzumab; Antibodies, Monoclonal, Humanized; Receptors, Estrogen; Injections, Subcutaneous; Adult; Neoplasm Metastasis; Middle Aged
PubMed: 38789924
DOI: 10.1186/s12885-024-12179-9 -
PloS One 2024Trastuzumab has significantly enhanced the survival and prognosis of individuals diagnosed with human epidermal growth factor receptor 2 (HER2)-positive early breast...
BACKGROUND
Trastuzumab has significantly enhanced the survival and prognosis of individuals diagnosed with human epidermal growth factor receptor 2 (HER2)-positive early breast cancer. Considering its relatively high costs, we aimed to examine the cost-effectiveness of trastuzumab plus chemotherapy compared with chemotherapy alone in HER2-positive early breast cancer from an Indonesian healthcare payer's perspective.
METHODS
A Markov model was developed to project the lifetime health benefits and costs associated with trastuzumab treatment for a cohort of women with HER2-positive early breast cancer. Efficacy data and baseline characteristics in the base-case analysis were primarily derived from the 11-year results of the HERA trial. Costs were based on verified reimbursement data from Indonesia's Health and Social Security Agency (BPJS Kesehatan) of the year 2020. A scenario analysis was conducted with efficacy data based on the joint analysis from the NSABP B-31 and NCCTG N9831 trials, allowing for subgroup analysis by age at diagnosis. Univariate and probabilistic sensitivity analyses were conducted to assess the influence of parameter uncertainty.
RESULTS
In the base-case analysis, the results indicated that the lifetime costs for trastuzumab plus chemotherapy and chemotherapy alone were US$33,744 and US$22,720, respectively, resulting in substantial incremental savings of US$11,024 per patient for the former. Trastuzumab plus chemotherapy also led to higher total quality-adjusted life years (QALYs) and life years gained (LYG), resulting in incremental cost-effectiveness ratios (ICERs) of US$6,842 per QALY and US$5,510 per LYG. In scenario analysis, the subgroup with an age at diagnosis <40 years old reflected the most cost-effective subgroup. Both the base-case and scenario analyses demonstrated cost-effectiveness with a willingness-to-pay threshold of three-times Gross Domestic Product (GDP). Sensitivity analyses confirmed the robustness of the findings and conclusions.
CONCLUSION
In Indonesia, trastuzumab plus chemotherapy can be considered cost-effective compared to chemotherapy alone at a willingness-to-pay threshold of three times GDP, and it is likely most cost-effective in women <40 years of age.
Topics: Humans; Trastuzumab; Breast Neoplasms; Female; Indonesia; Cost-Benefit Analysis; Receptor, ErbB-2; Quality-Adjusted Life Years; Middle Aged; Adult; Markov Chains; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Aged; Cost-Effectiveness Analysis
PubMed: 38787899
DOI: 10.1371/journal.pone.0304483 -
Therapeutic Advances in Urology 2024Antibody-drug conjugates and bicycle toxin conjugates represent a tremendous advance in drug delivery technology and have shown great promise in the treatment of... (Review)
Review
Antibody-drug conjugates and bicycle toxin conjugates represent a tremendous advance in drug delivery technology and have shown great promise in the treatment of urothelial cancer. Previously approved systemic therapies, including chemotherapy and immunotherapy, are often impractical due to comorbidities, and outcomes for patients with advanced disease remain poor, even when receiving systemic therapy. In this setting, antibody-drug and bicycle toxin conjugates have emerged as novel treatments, dramatically altering the therapeutic landscape. These drugs harness unique designs consisting of antibody or bicycle peptide, linker, and cytotoxic payload with more targeted delivery than conventional chemotherapy, thus eliminating malignant cells while reducing systemic toxicities. Potential targets investigated in urothelial cancer include Nectin-4, TROP2, HER2, and EphA2. Initial clinical trials demonstrated efficacy in treatment of refractory advanced urothelial cancer, as well as improvement in quality of life. These initial studies led to FDA approval of two antibody-drug conjugates, enfortumab vedotin and sacituzumab govitecan. Moreover, antibody-drug and bicycle toxin conjugates are being studied in ongoing clinical trials in frontline treatment of advanced disease as well as for localized cancer. These studies highlight the potential for additional future therapies with novel targets, novel antibodies, cytotoxic and immunomodulatory payloads, and unique structural designs enhancing efficacy and safety. There is increasing evidence that combinations with other cancer therapies, especially immunotherapy, improve treatment outcomes. The combination of enfortumab vedotin and pembrolizumab was recently approved for first-line treatment of advanced urothelial carcinoma. Despite the great promise of these novel drugs, robust predictive biomarkers are needed to determine the patients who would maximally benefit. This review surveys the rationale and current state of the evidence for these new drugs and describes future directions actively being explored.
PubMed: 38779496
DOI: 10.1177/17562872241249073 -
EJNMMI Radiopharmacy and Chemistry May 2024A significant challenge in cancer therapy lies in eradicating hidden disseminated tumor cells. Within Nuclear Medicine, Targeted Alpha Therapy is a promising approach...
BACKGROUND
A significant challenge in cancer therapy lies in eradicating hidden disseminated tumor cells. Within Nuclear Medicine, Targeted Alpha Therapy is a promising approach for cancer treatment tackling disseminated cancer. As tumor size decreases, alpha-particles gain prominence due to their high Linear Energy Transfer (LET) and short path length. Among alpha-particle emitters, At stands out with its 7.2 hour half-life and 100% alpha emission decay. However, optimizing the pharmacokinetics of radiopharmaceuticals with short lived radionuclides such as At is pivotal, and in this regard, pretargeting is a valuable tool. This method involves priming the tumor with a modified monoclonal antibody capable of binding both the tumor antigen and the radiolabeled carrier, termed the "effector molecule. This smaller, faster-clearing molecule improves efficacy. Utilizing the Diels Alder click reaction between Tetrazine (Tz) and Trans-cyclooctene (TCO), the Tz-substituted effector molecule combines seamlessly with the TCO-modified antibody. This study aims to evaluate the in vivo biodistribution of two Poly-L-Lysine-based effector molecule sizes (10 and 21 kDa), labelled with At, and the in vitro binding of the most favorable polymer size, in order to optimize the pretargeted radioimmunotherapy with At.
RESULTS
In vivo results favor the smaller polymer's biodistribution pattern over the larger one, which accumulates in organs like the liver and spleen. This is especially evident when comparing the biodistribution of the smaller polymer to a directly labelled monoclonal antibody. The smaller variant also shows rapid and efficient binding to SKOV-3 cells preloaded with TCO-modified Trastuzumab in vitro, emphasizing its potential. Both polymer sizes showed equal or better in vivo stability of the astatine-carbon bond compared to a monoclonal antibody labelled with the same prosthetic group.
CONCLUSIONS
Overall, the small Poly-L-Lysine-based effector molecule (10 kDa) holds the most promise for future research, exhibiting significantly lower uptake in the kidneys and spleen compared to the larger effector (21 kDa) while maintaining an in vivo stability of the astatine-carbon bond comparable to or better than intact antibodies. A proof of concept in vitro cell study demonstrates rapid reaction between the small astatinated effector and a TCO-labelled antibody, indicating the potential of this novel Poly-L-Lysine-based pretargeting system for further investigation in an in vivo tumor model.
PubMed: 38775973
DOI: 10.1186/s41181-024-00273-z -
Frontiers in Oncology 2024Patients with metastatic HER2-positive breast cancer have multiple therapeutic options. However, most are not studied in the renal replacement therapy (RRT) setting.
INTRODUCTION
Patients with metastatic HER2-positive breast cancer have multiple therapeutic options. However, most are not studied in the renal replacement therapy (RRT) setting.
CASE REPORT
We report the use of Phesgo® (subcutaneous fixed-dose combination of trastuzumab and pertuzumab) combined with exemestane as a first-line treatment of metastatic HER2-positive breast cancer in a hemodialysis patient with multiple comorbidities. Partial response was attained, with disease progression after 8 months without evidence of significant toxicity.
DISCUSSIONS
This case report is, to our knowledge, the first published case documenting the use of Phesgo® in a hemodialysis patient. No new safety signs were seen, and activity was documented, adding support to the use of this drug combination in such a patient population.
PubMed: 38774415
DOI: 10.3389/fonc.2024.1348343 -
Bulletin Du Cancer May 2024Therapeutic options for breast cancer have recently been enriched by new antibody-drug conjugates (ADC), which are now being utilized across all known molecular... (Review)
Review
Therapeutic options for breast cancer have recently been enriched by new antibody-drug conjugates (ADC), which are now being utilized across all known molecular subtypes. ADCs represent a groundbreaking class of therapies that combine a cytotoxic agent with a monoclonal antibody via a combination molecule (linker). The primary objective is to selectively deliver chemotherapy to cells expressing the target antigen, thereby enhancing the therapeutic index. Trastuzumab-emtansine marked the pioneering use of this approach for HER2-overexpressed breast cancer. More recently, trastuzumab-deruxtecan and sacituzumab-govitecan have demonstrated efficacy in progression-free survival and overall survival in HER2-overexpressed and HER2-low breast cancer for the former, and HER2-non-overexpressed (including HER-low) for the latter. Numerous other ADCs are currently under development in breast cancer. While ADCs were initially designed to widen the therapeutic index and mitigate toxicities, managing ADC-related adverse events in the clinical setting remains a challenge. This review article aims to provide an overview of the toxicity profiles of these drugs already in current clinical practice or under development, drawing from results observed in various studies.
PubMed: 38772845
DOI: 10.1016/j.bulcan.2024.04.004 -
Frontiers in Oncology 2024The overamplification of human epidermal growth factor (HER2) in breast cancer (BC) has been the subject of numerous research publications since its discovery in 1987.... (Review)
Review
AIM
The overamplification of human epidermal growth factor (HER2) in breast cancer (BC) has been the subject of numerous research publications since its discovery in 1987. This is the first bibliometric analysis (BA) conducted on HER2-positive (HER2+) BC. The purpose of this BA is to analyze the published research on HER2+ BC from 1987 to 2024, highlighting the most significant scientific literature, as well as the main contributing authors and journals, and evaluating the impact of clinical and lab-based publications on HER2+ BC research.
METHODS
The Web of Science Core Collection (WoSCC) was searched using the terms "Breast cancer" OR "Breast carcinoma" OR "Breast tumor" AND "HER2 positive" OR "HER2+". The search was limited by publication year (1987-2024) and only full English articles were included. WoS returned 7,469 relevant results, and from this dataset, a bibliometric analysis was conducted using the "analyze results" and "journal citation report" functions in WoS and the VOSviewer 1.6.16 software to generate bibliographic coupling and co-citation analysis of authors.
RESULTS
The analysis encompassed a total of 7,469 publications, revealing a notable increase in the annual number of publications, particularly in recent years. The United States, China, Italy, Germany, and Spain were the top five most prolific countries. The top five significant institutions that published HER2+ research were the University of Texas System, Unicancer, UTMD Anderson Cancer Center, Harvard University, and University of California System. , , and were the top three notable journals with the highest number of HER2+ BC publications. Dennis Slamon (Nc = 45,411, H-index = 51) and Jose Baselga (Nc = 32,592, H-index = 55) were the most prolific authors. Evolving research topics include anti-HER2 therapy in the neoadjuvant setting, treatment of metastatic HER2+ BC, and overcoming therapy resistance.
CONCLUSION
This study provides an overview of HER2+ BC research published over the past three decades. It provides insight into the most cited papers and authors, and the core journals, and identifies new trends. These manuscripts have had the highest impact in the field and reflect the continued evolution of HER2 as a therapeutic target in BC.
PubMed: 38769947
DOI: 10.3389/fonc.2024.1355353 -
Journal of Breast Cancer Apr 2024The global incidence of breast cancer is on the rise, a trend also observed in South Korea. However, thanks to the rapid advancements in anticancer therapies, survival... (Review)
Review
The global incidence of breast cancer is on the rise, a trend also observed in South Korea. However, thanks to the rapid advancements in anticancer therapies, survival rates are improving. Consequently, post-treatment health and quality of life for breast cancer survivors are emerging as significant concerns, particularly regarding treatment-related cardiotoxicity. In this review, we delve into the cardiovascular complications associated with breast cancer treatment, explore surveillance protocols for early detection and diagnosis of late complications, and discuss protective strategies against cardiotoxicity in breast cancer patients undergoing anticancer therapy, drawing from multiple guidelines.
PubMed: 38769686
DOI: 10.4048/jbc.2024.0085 -
Frontiers in Pharmacology 2024As a novel drug formulation, antibody drug conjugates (ADCs) are widely used in various types of cancer. However, clinically, there is a lack of attention to the CVD...
OBJECTIVE
As a novel drug formulation, antibody drug conjugates (ADCs) are widely used in various types of cancer. However, clinically, there is a lack of attention to the CVD produced by them, as well as a lack of research on the real-world situation. Using the Food and Drug Administration Adverse Event Reporting System (FAERS) database, to ensure its clinical safety application, we analyzed post-marketing data on antitumor ADCs to identify risk factors and drugs associated with the risk of cardiovascular events.
RESEARCH DESIGN AND METHODS
We used OpenVigil 2.1 to conduct a database query for adverse events (AEs) reported to the FAERS database between the time the drug was launched and the second quarter of 2023. Cardiovascular adverse events (AEs) were grouped into fourteen narrow categories using the Standardized Medical Dictionary for Regulatory Activities (MedDRA) Queries (SMQs), and the reporting odds ratio (ROR) and the proportional reporting ratio (PRR) for reporting the association between different drugs and cardiovascular disease (CVD) risk were calculated.
RESULTS
In the FAERS database, 1863 AEs associated with CVD we studied were identified in patients receiving ADC therapy. Most reports came from people aged ≥65, but a significant number of cases were found to be unknown. The number of patients with antibody-drug conjugates (ADCs)-related CVD cases aged <18 years, 18-64 years, and≥ 65 years was 52 (2.79%), 586 (31.45%), and 613 (32.90%), respectively. The proportion of female patients (834, 44.77%) was higher than that of male patients (752, 40.37%). Death (770 reports), disability (9 reports), Hospitalization initial or prolonged (407 reports), and life-threatening reactions (187 reports). Of the 770 deaths reported, 103 (31.7%) were associated with brentuximab vedotin, 10 (24.4%) with sacituzumab govitecan, 22 (19.3%) with enfortumab vedotin, and 35 (34.7%) with trastuzumab emtansine.49 (41.2%) cases were associated with polatuzumab vedotin, 62 (29%) with trastuzumab deruxtecan, 423 (54.3%) with gemtuzumab ozogamicin, and 66 (38.8%) with inotuzumab ozogamicin. In a disproportionate number of SMQS, cardiac failure ( = 277) and embolic and thrombotic events, venous ( = 446) were the most frequently reported CVD-related AEs in ADCs.
CONCLUSION
By mining the FAERS database, we provided relevant information on the association between ADC use and cardiovascular-associated AEs. ADCs were associated with increased cardiovascular toxicity, deserving distinct monitoring and appropriate management. Further research is needed to confirm these findings and assess causality.
PubMed: 38766629
DOI: 10.3389/fphar.2024.1378010