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-Reference-Cited by-同舟云学术

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

Published:2023-10-27 Issue:24 Volume:29 Page:5217-5226
ISSN:1078-0432
Container-title:Clinical Cancer Research
language:en
Short-container-title:

Author:

Conte Benedetta¹²³^ORCID,Boni Luca⁴^ORCID,Bisagni Giancarlo⁵^ORCID,Durando Antonio⁶^ORCID,Sanna Giovanni⁷^ORCID,Gori Stefania⁸^ORCID,Garrone Ornella⁹¹⁰^ORCID,Tamberi Stefano¹¹^ORCID,De Placido Sabino¹²^ORCID,Schettini Francesco¹²¹³^ORCID,Pazzola Antonio¹⁴^ORCID,Ponzone Riccardo¹⁵^ORCID,Montemurro Filippo¹⁵^ORCID,Lunardi Gianluigi¹⁶^ORCID,Notaro Rosario¹⁷^ORCID,De Angioletti Maria¹⁷¹⁸^ORCID,Turletti Anna¹⁹^ORCID,Mansutti Mauro²⁰^ORCID,Puglisi Fabio²¹²²^ORCID,Frassoldati Antonio²³^ORCID,Porpiglia Mauro²⁴^ORCID,Fabi Alessandra²⁵^ORCID,Generali Daniele²⁶²⁷^ORCID,Scognamiglio Giovanni²⁸^ORCID,Rossi Maura²⁹^ORCID,Brasó-Maristany Fara¹^ORCID,Prat Aleix¹²¹²³⁰³¹^ORCID,Cardinali Barbara³²^ORCID,Piccioli Patrizia³²^ORCID,Serra Martina³³^ORCID,Lastraioli Sonia³⁴^ORCID,Bighin Claudia³⁵^ORCID,Poggio Francesca³⁵^ORCID,Lambertini Matteo³²³⁶^ORCID,Del Mastro Lucia³²³⁶^ORCID

Affiliation:

1. 1Translational Genomics and Targeted Therapies in Solid Tumors, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain.

2. 2Department of Medical Oncology, Hospital Clinic of Barcelona, Barcelona, Spain.

3. 3Universitat de Barcelona, Barcelona, Spain.

4. 4S.C. Epidemiologia Clinica, IRCCS Ospedale Policlinico San Martino, Genova, Italy.

5. 5Azienda unità Sanitaria Locale – IRCCS di Reggio Emilia, Reggio Emilia, Italy.

6. 6Breast Unit Ospedale S Anna, Citta' della Salute e della Scienza di Torino, Torino, Italy.

7. 7Azienda Ospedaliera Universitaria – Sassari, Sassari, Italy.

8. 8UOC Oncologia Medica, IRCCS Ospedale Sacro Cuore Don Calabria, Negrar, Verona, Italy.

9. 9Breast Unit, AO S. Croce e Carle Ospedale di insegnamento, Cuneo, Italy.

10. 10Medical Oncology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano, Milano.

11. 11UO Oncologia, Ospedale degli Infermi, Faenza, Italy.

12. 12Department of Clinical Medicine and Surgery, University of Naples Federico II, Napoli, Italy.

13. 13Departament de Medicina, Facultat de Medicina i Ciències de la Salut, Universitat de Barcelona, Spain.

14. 14Azienda Ospedaliera Universitaria – Sassari, Sassari, Italy.

15. 15Candiolo Cancer Institute, FPO-IRCCS, Gynecologic Oncology and Multidisciplinary Outpatient Oncology Clinic, Candiolo, Italy.

16. 16Laboratorio Analisi Chimico-Cliniche, IRCCS-Ospedale Sacro Cuore Don Calabria, Negrar, Verona, Italy.

17. 17Core Research Laboratory-ISPRO, Firenze, Italy.

18. 18National Research Council (CNR) - ICCOM, Firenze, Italy.

19. 19Breast Unit, ASL Citta' di Torino, Torino, Italy.

20. 20Department of Oncology, ASUFC Santa Maria della Misericordia, Udine, Italy.

21. 21Department of Medicine, University of Udine, Udine, Italy.

22. 22Depatment of Medical Oncology, Centro di Riferimento Oncologico di Aviano IRCCS, Aviano, Italy.

23. 23Department of Morphology, Surgery and Experimental medicine, Clinical Oncology, St. Anna University Hospital, Ferrara, Italy.

24. 24Breast Unit Ospedale S. Anna, AOU Città della Salute e della Scienza di Torino, Torino, Italy.

25. 25Medical Oncology, IRCCS Regina Elena National Cancer Institute, Roma, Italy.

26. 26Medical Oncology, Azienda Istituti Ospitalieri di Cremona, Cremona, Italy.

27. 27Department of Medicine, Surgery and Health Sciences, University of Trieste, Trieste, Italy.

28. 28Oncologia Medica, Ospedale Valduce, Como, Italy.

29. 29SOC Oncologia, ASO SS.Antonio e Biagio, Alessandria, Italy.

30. 30Reveal Genomics, Barcelona, Spain.

31. 31Institute of Oncology (IOB)-Hospital Quirónsalud, Barcelona, Spain.

32. 32Medical Oncology Department, U.O. Clinica di Oncologia Medica, IRCCS Ospedale Policlinico San Martino, Genova, Italy.

33. 33Laboratory of Clinical and Experimental Immunology, IRCCS Istituto Giannina Gaslini, Genoa, Italy.

34. 34Molecular Diagnostic Unit, IRCCS Ospedale Policlinico San Martino, Genoa, Italy.

35. 35Medical Oncology Department 2, IRCCS Ospedale Policlinico San Martino, Genova, Italy.

36. 36Department of Internal Medicine and Medical Specialties (DiMI), School of Medicine, University of Genova, Genova, Italy.

Abstract

Abstract Purpose: 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. Experimental Design: 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. Results: 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). Conclusions: SNP of aromatase gene predict risk of metastasis and AI-related toxicity in ER+ early breast cancer, opening an opportunity for better treatment individualization.

Funder

Ministero della Salute

HORIZON EUROPE European Research Council

Publisher

American Association for Cancer Research (AACR)

Subject

Cancer Research,Oncology

Link

https://aacrjournals.org/clincancerres/article-pdf/doi/10.1158/1078-0432.CCR-23-1568/3375914/ccr-23-1568.pdf

Reference38 articles.

1. 20-year risks of breast-cancer recurrence after stopping endocrine therapy at 5 years;Pan;N Engl J Med,2017

2. Effects of prolonging adjuvant aromatase inhibitor therapy beyond five years on recurrence and cause-specific mortality: an EBCTCG meta-analysis of individual patient data from 12 randomised trials including 24,912 women;Gray,2019

3. Biomarkers for adjuvant endocrine and chemotherapy in early-stage breast cancer: ASCO guideline update;Andre;J Clin Oncol,2022

4. Tailoring the optimal duration of the extended adjuvant endocrine therapy in patients with early-stage breast cancer. A systematic review and meta-analysis of randomized clinical trials;Pala;The Breast,2023

5. Duration of adjuvant aromatase-inhibitor therapy in postmenopausal breast cancer;Gnant;N Engl J Med,2021