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Supplementary Tables S9 from SNP of Aromatase Predict Long-term Survival and Aromatase Inhibitor Toxicity in Patients with Early Breast Cancer: A Biomarker Analysis of the GIM4 and GIM5 Trials

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posted on 2023-12-15, 08:41 authored by Benedetta Conte, Luca Boni, Giancarlo Bisagni, Antonio Durando, Giovanni Sanna, Stefania Gori, Ornella Garrone, Stefano Tamberi, Sabino De Placido, Francesco Schettini, Antonio Pazzola, Riccardo Ponzone, Filippo Montemurro, Gianluigi Lunardi, Rosario Notaro, Maria De Angioletti, Anna Turletti, Mauro Mansutti, Fabio Puglisi, Antonio Frassoldati, Mauro Porpiglia, Alessandra Fabi, Daniele Generali, Giovanni Scognamiglio, Maura Rossi, Fara Brasó-Maristany, Aleix Prat, Barbara Cardinali, Patrizia Piccioli, Martina Serra, Sonia Lastraioli, Claudia Bighin, Francesca Poggio, Matteo Lambertini, Lucia Del Mastro

Univariate analyses for DFS in GIM5, GIM4 short arm, and GIM4 long arm cohorts

Funding

Ministero della Salute (Italy Ministry of Health)

HORIZON EUROPE European Research Council (ERC)

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ARTICLE ABSTRACT

In estrogen receptor–positive (ER+) breast cancer, single-nucleotide polymorphisms (SNP) in the aromatase gene might affect aromatase inhibitors (AI) metabolism and efficacy. Here, we assessed the impact of SNP on prognosis and toxicity of patients receiving adjuvant letrozole. We enrolled 886 postmenopausal patients in the study. They were treated with letrozole for 2 to 5 years after taking tamoxifen for 2 to 6 years, continuing until they completed 5 to 10 years of therapy. Germline DNA was genotyped for SNP rs4646, rs10046, rs749292, and rs727479. Log-rank test and Cox model were used for disease-free survival (DFS) and overall survival (OS). Cumulative incidence (CI) of breast cancer metastasis was assessed through competing risk analysis, with contralateral breast cancer, second malignancies and non-breast cancer death as competing events. CI of skeletal and cardiovascular events were assessed using DFS events as competing events. Subdistribution HR (sHR) with 95% confidence intervals were calculated through Fine-Gray method. No SNP was associated with DFS. Variants rs10046 [sHR 2.03, (1.04–2.94)], rs749292 [sHR 2.11, (1.12–3.94)], and rs727479 [sHR 2.62, (1.17–5.83)] were associated with breast cancer metastasis. Three groups were identified on the basis of the number of these variants (0, 1, >1). Variant-based groups were associated with breast cancer metastasis (10-year CI 2.5%, 7.6%, 10.7%, P = 0.035) and OS (10-year estimates 96.5%, 93.0%, 89.6%, P = 0.030). Co-occurrence of rs10046 and rs749292 was negatively associated with 10-year CI of skeletal events (3.2% vs. 10%, P = 0.033). A similar association emerged between rs727479 and cardiovascular events (0.3% vs. 2.1%, P = 0.026). SNP of aromatase gene predict risk of metastasis and AI-related toxicity in ER+ early breast cancer, opening an opportunity for better treatment individualization.

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    Clinical Cancer Research

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    Keywords

    BiomarkersPrognostic biomarkersBreast CancerDrug ResistanceNovel mechanismsPharmacologyMolecular pharmacologyPrecision MedicineSurvivorship ResearchTranslational Research

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