Purpose: Prognostic and predictive biomarkers to cyclin-dependent kinases 4 and 6 inhibitors are lacking. Circulating tumor DNA (ctDNA) can be used to profile these patients and dynamic changes in ctDNA could be an early predictor of treatment efficacy. Here, we conducted plasma ctDNA profiling in patients from the PEARL trial comparing palbociclib+fulvestrant versus capecitabine to investigate associations between baseline genomic landscape and on-treatment ctDNA dynamics with treatment efficacy.
Experimental Design: Correlative blood samples were collected at baseline [cycle 1-day 1 (C1D1)] and prior to treatment [cycle 1-day 15 (C1D15)]. Plasma ctDNA was sequenced with a custom error-corrected capture panel, with both univariate and multivariate Cox models used for treatment efficacy associations. A prespecified methodology measuring ctDNA changes in clonal mutations between C1D1 and C1D15 was used for the on-treatment ctDNA dynamic model.
Results: 201 patients were profiled at baseline, with ctDNA detection associated with worse progression-free survival (PFS)/overall survival (OS). Detectable TP53 mutation showed worse PFS and OS in both treatment arms, even after restricting population to baseline ctDNA detection. ESR1 mutations were associated with worse OS overall, which was lost when restricting population to baseline ctDNA detection. PIK3CA mutations confer worse OS only to patients on the palbociclib+fulvestrant treatment arm. ctDNA dynamics analysis (n = 120) showed higher ctDNA suppression in the capecitabine arm. Patients without ctDNA suppression showed worse PFS in both treatment arms.
Conclusions: We show impaired survival irrespective of endocrine or chemotherapy-based treatments for patients with hormone receptor-positive/HER2-negative metastatic breast cancer harboring plasma TP53 mutations. Early ctDNA suppression may provide treatment efficacy predictions. Further validation to fully demonstrate clinical utility of ctDNA dynamics is warranted.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10570672 | PMC |
| http://dx.doi.org/10.1158/1078-0432.CCR-23-0956 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Neoadjuvant darolutamide plus androgen deprivation therapy for high-risk and locally advanced prostate cancer: a multicenter, open-label, single-arm, phase II trial.
World J Urol
January 2025
Department of Urology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China.
Propose: This study aimed to evaluate the efficacy and safety of neoadjuvant treatment of darolutamide, a next-generation androgen receptor inhibitor, plus androgen deprivation therapy (ADT) for patients with locally advanced prostate cancer (LAPC).
Methods: This single-arm, multicenter, open-label phase II trial (ClinicalTrials.gov: NCT05249712, 2022-01-01), recruited 30 localized high-risk/very high-risk prostate cancer (HRPCa/VHRPCa) patients from three centers in China between 2021 and 2023.
Detection of H3F3A K27M or BRAF V600E in liquid biopsies of brain tumor patients as diagnostic and monitoring biomarker: impact of tumor localization and sampling method.
Acta Neuropathol
January 2025
Department of Pediatrics and Adolescent Medicine, Comprehensive Center for Pediatrics and Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.
Gliomas are the most common brain tumor type in children and adolescents. To date, diagnosis and therapy monitoring for these tumors rely on magnetic resonance imaging (MRI) and histopathological as well as molecular analyses of tumor tissue. Recently, liquid biopsies (LB) have emerged as promising tool for diagnosis and longitudinal tumor assessment potentially allowing for a more precise therapeutic management.
View Article and Find Full Text PDFImpact of Higher Cell-Free DNA Yields on Liquid Biopsy Testing in Glioblastoma Patients.
Clin Chem
January 2025
Broad Institute of MIT and Harvard, Cambridge, MA, United States.
Background: Minimally invasive molecular profiling using cell-free DNA (cfDNA) is increasingly important to the management of cancer patients; however, low sensitivity remains a major limitation, particularly for brain tumor patients. Transiently attenuating cfDNA clearance from the body-thereby, allowing more cfDNA to be sampled-has been proposed to improve the performance of liquid biopsy diagnostics. However, there is a paucity of clinical data on the effect of higher cfDNA recovery.
View Article and Find Full Text PDFBackground: Multi-cancer early detection (MCED) through a single blood test significantly advances cancer diagnosis. However, most MCED tests rely on a single type of biomarkers, leading to limited sensitivity, particularly for early-stage cancers. We previously developed SPOT-MAS, a multimodal ctDNA-based assay analyzing methylation and fragmentomic profiles to detect five common cancers.
View Article and Find Full Text PDFThe clinical utility of circulating human papillomavirus across squamous cell carcinomas.
Acta Oncol
January 2025
Department of Experimental Clinical Oncology, Aarhus University Hospital, Aarhus, Denmark; Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
Background And Purpose: The similarities in biology, treatment regimens and outcome between the different human papillomavirus (HPV) associated squamous cell carcinomas (SCCs) allow for extrapolation of results generated from one SC tumor type to another. In HPV associated cancers, HPV is integrated into the tumor genome and can consequently be detected in the circulating fragments of the tumor DNA. Thus, measurement of HPV in the plasma is a surrogate for circulating tumor DNA (ctDNA) and holds promise as a clinically relevant biomarker in HPV associated cancers.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!