Baseline mutations and ctDNA dynamics as prognostic and predictive factors in ER-positive/HER2-negative metastatic breast cancer patients
Pascual, Javier ; Gil-Gil, Miguel ; Proszek, Paula ; Zielinski, Christoph ; Reay, Alistair ; Ruiz-Borrego, Manuel ; Cutts, Rosalind ; Ciruelos Gil, Eva M. ; Feber, Andrew ; Muñoz-Mateu, Montserrat ; Swift, Claire ; Bermejo, Begoña ; Herranz, Jesus ; Margeli Vila, Mireia ; Antón, Antonio (Universidad de Zaragoza) ; Kahan, Zsuzsanna ; Csöszi, Tibor ; Liu, Yuan ; Fernandez-Garcia, Daniel ; Garcia-Murillas, Isaac ; Hubank, Michael ; Turner, Nicholas C. ; Martín, Miguel
Resumen: 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.
Idioma: Inglés
DOI: 10.1158/1078-0432.CCR-23-0956
Año: 2023
Publicado en: CLINICAL CANCER RESEARCH 29, 20 (2023), 4166-4177
ISSN: 1078-0432
Factor impacto JCR: 10.4 (2023)
Categ. JCR: ONCOLOGY rank: 26 / 322 = 0.081 (2023) - Q1 - T1
Factor impacto CITESCORE: 20.1 - Cancer Research (Q1) - Oncology (Q1)
Factor impacto SCIMAGO: 4.623 - Oncology (Q1) - Cancer Research (Q1)
Tipo y forma: Article (Published version)
Área (Departamento): Area Medicina (Dpto. Medicina, Psiqu. y Derm.)
You must give appropriate credit, provide a link to the license, and indicate if changes were made. You may do so in any reasonable manner, but not in any way that suggests the licensor endorses you or your use. You may not use the material for commercial purposes. If you remix, transform, or build upon the material, you may not distribute the modified material.
Exportado de SIDERAL (2024-11-22-12:09:13)
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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.
Idioma: Inglés
DOI: 10.1158/1078-0432.CCR-23-0956
Año: 2023
Publicado en: CLINICAL CANCER RESEARCH 29, 20 (2023), 4166-4177
ISSN: 1078-0432
Factor impacto JCR: 10.4 (2023)
Categ. JCR: ONCOLOGY rank: 26 / 322 = 0.081 (2023) - Q1 - T1
Factor impacto CITESCORE: 20.1 - Cancer Research (Q1) - Oncology (Q1)
Factor impacto SCIMAGO: 4.623 - Oncology (Q1) - Cancer Research (Q1)
Tipo y forma: Article (Published version)
Área (Departamento): Area Medicina (Dpto. Medicina, Psiqu. y Derm.)
You must give appropriate credit, provide a link to the license, and indicate if changes were made. You may do so in any reasonable manner, but not in any way that suggests the licensor endorses you or your use. You may not use the material for commercial purposes. If you remix, transform, or build upon the material, you may not distribute the modified material. Exportado de SIDERAL (2024-11-22-12:09:13)
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Record created 2024-02-19, last modified 2024-11-25