Abstract
Clinico-molecular characteristics associated with outcomes in breast cancer patients treated with CDK4/6 inhibitors: Results from the AURORA Molecular Screening Initiative.
Author
person
Elisa Agostinetto
Institut Jules Bordet and Université Libre de Bruxelles (U.L.B), Brussels, Belgium
info_outline
Elisa Agostinetto, Christos Sotiriou, Michail Ignatiadis, Thayane Antoniolli Crestani, David Venet, Svitlana Tyekucheva, Alexandre Irrthum, Jose A. Seoane, Martine J. Piccart-Gebhart, David A. Cameron, Susan Knox, CRISTINA EMILIA ROTARU, Dario Romagnoli, Gabriele Zoppoli, Philippe Georges Aftimos, Mafalda Oliveira, Meredith M. Regan, Luca Malorni, Matteo Benelli, Florentine Hilbers
Full text
Authors
person
Elisa Agostinetto
Institut Jules Bordet and Université Libre de Bruxelles (U.L.B), Brussels, Belgium
info_outline
Elisa Agostinetto, Christos Sotiriou, Michail Ignatiadis, Thayane Antoniolli Crestani, David Venet, Svitlana Tyekucheva, Alexandre Irrthum, Jose A. Seoane, Martine J. Piccart-Gebhart, David A. Cameron, Susan Knox, CRISTINA EMILIA ROTARU, Dario Romagnoli, Gabriele Zoppoli, Philippe Georges Aftimos, Mafalda Oliveira, Meredith M. Regan, Luca Malorni, Matteo Benelli, Florentine Hilbers
Organizations
Institut Jules Bordet and Université Libre de Bruxelles (U.L.B), Brussels, Belgium, Department of Medical Oncology and Breast Cancer Translational Research Laboratory, Institut Jules Bordet, Brussels, Belgium, Department of Medical Oncology and Academic Trials Promoting Team, Institut Jules Bordet and l’Université Libre de Bruxelles (U.L.B.), Brussels, Belgium, Breast International Group (BIG), Brussels, Belgium, Breast Cancer Translational Research Laboratory, Institut Jules Bordet, Brussels, Belgium, Department of Data Science, Dana-Farber Cancer Institute, Boston, MA, Breast International Group, Brussels, Belgium, Cancer Computational Biology Group. Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain, Institut Jules Bordet, Université Libre de Bruxelles (U.L.B.), Brussels, Belgium, Edinburgh University Cancer Centre, Edinburgh, Scotland, United Kingdom, Europa Donna-The European Breast Cancer Coalition, Milan, Italy, Bioinformatic Unit, Hospital of Prato, Istituto Toscano Tumori, Prato, Italy, University of Genova, Genova, Italy, Medical Oncology Department, Institut Jules Bordet and l’Université Libre de Bruxelles (U.L.B), Brussels, Belgium, Brussels, Belgium, Vall d’Hebron University Hospital and Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain, Dana-Farber Cancer Institute, Boston, MA, Department of Oncology and Translational Research Unit "Sandro Pitigliani", Ospedale di Prato, Azienda USL Toscana Centro, Prato, Italy, Bioinformatics Unit, Hospital of Prato, Prato, Italy, Department of Molecular Pathology, Netherlands Cancer Institute, Amsterdam, Netherlands
Abstract Disclosures
Research Funding
Other Foundation
AURORA was funded by Breast Cancer Research Foundation (BCRF) as the main funder, Fondation Cancer (Luxembourg), Fondation contre le Cancer (Belgium), NIF Foundation, Barrie and Dena Webb, Candriam, Fondation Futur 21, Sogerim, Think Pink Belgium (SMART Fund), Cognizant Foundation, Eurofins Foundation, Fund Friends of BIG, managed by the King Baudouin Foundation, Pfizer grant for non-drug research, National Lottery (Belgium)
Background:
CDK4/6 inhibitor (CDK4/6i) plus endocrine therapy (ET) is the recommended first line standard of care for patients with estrogen receptor positive (ER+), HER2-negative (HER2-) advanced breast cancer (ABC). However, not all patients derive the same benefit from this treatment. We aimed to identify factors associated with outcome in patients treated with CDK4/6i in a real-world setting.
Methods:
AURORA (NCT02102165) is an international program aimed at studying ABC by performing multi-omics profiling on paired primary tumors and metastases. Here we present exploratory results from AURORA patients treated with first line CDK4/6i + ET. DNA from primary and/or metastatic lesions and germline DNA was sequenced for 411 cancer-related genes. Endocrine resistance was defined according to the 5th ABC international consensus guidelines at the start of the first line. Local histology assessment of the primary tumor was used. Progression-free survival (PFS) was calculated from the start of CDK4/6i treatment until disease progression or death (whichever occurred first).
Results:
We analyzed 339 patients treated with CDK4/6i + ET in the first line. PFS differed significantly among the endocrine resistance subgroups (p<0.001). Both TP53 and acquired ESR1 mutations were associated with shorter PFS (hazard ratio [HR] 1.59 [95% CI 1.43-6.73], p=0.004 and 3.10 [95% CI 1.16-2.18], p=0.004 respectively). In a multivariable analysis, acquired ESR1 mutations were significantly associated with worse PFS independently of endocrine resistance status (HR 2.42 [95% CI 1.01-5.79], p=0.048). Mutations in PIK3CA were not associated with outcome (HR 0.84 [95% CI 0.63-1.13], p=0.25). No PFS difference was observed between lobular and ductal tumors (HR 1.07 [95% CI 0.66-1.75], p=0.61).
Conclusions:
Endocrine resistance status and TP53 and acquired ESR1 mutations were associated with shorter PFS. Factors associated with poor outcome may be used to select patients to test alternative treatment strategies in clinical trials. Clinical trial information: NCT02102165.
Subgroup n (%) PFS events Median PFS months (95% CI)
All 339 (100) 194 19.5 (15.9-21.6)
Primary resistant 26 (8) 20 6.6 (3.6-NE)
Secondary resistant 124 (37) 79 14.6 (12.3-19.3)
Endocrine sensitive 93 (27) 48 26.3 (18.6-39.0)
Endocrine Naive 96 (28) 47 27.3 (21.0-40.0)
PIK3CA mutated 137 (40) 73 20.4 (15.6-30.9)
TP53 mutated 79 (23) 54 14.0 (10.8-19.4)
acquired ESR1 mutated* 11 (11) 8 11.7 (3.8-NE)
Lobular 51 (15) 33 19.6 (14.7-26.5)
*Paired samples only (n=96).
27 organizations
4 drugs
5 targets
Organization
Université Libre de Bruxelles (ULB)Organization
Breast International Group, Brussels, BelgiumOrganization
Dana-Farber Cancer InstituteOrganization
Vall d’Hebron Institute of Oncology (VHIO)Organization
Hospital of PratoOrganization
University of Genova, Genova, ItalyOrganization
Vall d’Hebron University Hospital/VHIOOrganization
Translational Research UnitOrganization
Ospedale di PratoOrganization
Academic Trials Promoting TeamOrganization
Department of Data SciencesOrganization
Cancer Computational Biology Group, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, SpainOrganization
Edinburgh University Cancer CentreOrganization
Bioinformatic UnitOrganization
Istituto Toscano TumoriOrganization
Medical Oncology DepartmentOrganization
Sandro PitiglianiOrganization
Azienda USL Toscana CentroOrganization
Netherlands Cancer InstituteOrganization
Université Libre de Bruxelles (U.L.B)Organization
Breast International Group (BIG)Drug
CDK4/6iDrug
etoposideTarget
CDK6Target
TP53Target
ESR1 mutationTarget
PIK3CATarget
CDK4 & 6