Development and validation of the new HER2DX assay for predicting pathological response and survival outcome in early-stage HER2-positive breast cancer
Aleix Prat,
Valentina Guarneri,
Tomás Pascual,
Fara Brasó-Maristany,
Esther Sanfeliu,
Laia Paré,
Francesco Schettini,
Débora Martínez,
Pedro Jares,
Gaia Griguolo,
Maria Vittoria Dieci,
Javier Cortés,
Antonio Llombart-Cussac,
Benedetta Conte,
Mercedes Marín-Aguilera,
Nuria Chic,
Joan Anton Puig-Butillé,
Antonio Martínez,
Patricia Galván,
Yi-Hsuan Tsai,
Blanca González-Farré,
Aurea Mira,
Ana Vivancos,
Patricia Villagrasa,
Joel S. Parker,
Pierfranco Conte,
Charles M. Perou
Affiliations
Aleix Prat
Translational Genomics and Targeted Therapies in Solid Tumors, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain; Department of Medical Oncology, Hospital Clinic of Barcelona, Spain; SOLTI cooperative group, Barcelona, Spain; Department of Medicine, University of Barcelona, Barcelona, Spain; Institute of Oncology (IOB)-Hospital Quirónsalud, Barcelona, Spain; Corresponding author at: Translational Genomic and Targeted Therapies in Solid Tumors, August Pi i Sunyer Biomedical Research Institute (IDIBAPS) and Department of Medical Oncology, Hospital Clinic, Carrer de Villarroel, 170, 08036, Barcelona, Spain.
Valentina Guarneri
Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy; Medical Oncology 2, Istituto Oncologico Veneto, IRCCS, Padova, Italy
Tomás Pascual
SOLTI cooperative group, Barcelona, Spain
Fara Brasó-Maristany
Translational Genomics and Targeted Therapies in Solid Tumors, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain
Esther Sanfeliu
Translational Genomics and Targeted Therapies in Solid Tumors, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain; Department of Pathology, Hospital Clinic de Barcelona, Barcelona, Spain
Laia Paré
Reveal Genomics, Barcelona, Spain
Francesco Schettini
Translational Genomics and Targeted Therapies in Solid Tumors, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain; Department of Medical Oncology, Hospital Clinic of Barcelona, Spain; SOLTI cooperative group, Barcelona, Spain
Débora Martínez
Translational Genomics and Targeted Therapies in Solid Tumors, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain
Pedro Jares
Department of Pathology, Hospital Clinic de Barcelona, Barcelona, Spain; Molecular Biology CORE laboratory, Hospital Clinic de Barcelona, Barcelona, Spain
Gaia Griguolo
Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy; Medical Oncology 2, Istituto Oncologico Veneto, IRCCS, Padova, Italy
Maria Vittoria Dieci
Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy; Medical Oncology 2, Istituto Oncologico Veneto, IRCCS, Padova, Italy
Javier Cortés
Institute of Oncology (IOB)-Quiron, Madrid, Spain; Vall d´Hebron Institute of Oncology (VHIO), Barcelona, Spain
Antonio Llombart-Cussac
Department of Medical Oncology, Hospital Arnau de Vilanova, Valencia, Spain
Benedetta Conte
Translational Genomics and Targeted Therapies in Solid Tumors, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain; Department of Medical Oncology, Hospital Clinic of Barcelona, Spain; SOLTI cooperative group, Barcelona, Spain
Mercedes Marín-Aguilera
Reveal Genomics, Barcelona, Spain
Nuria Chic
Translational Genomics and Targeted Therapies in Solid Tumors, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain; Department of Medical Oncology, Hospital Clinic of Barcelona, Spain; SOLTI cooperative group, Barcelona, Spain
Joan Anton Puig-Butillé
Molecular Biology CORE laboratory, Hospital Clinic de Barcelona, Barcelona, Spain; Biochemistry and Molecular Genetics Service, Hospital Clinic de Barcelona, Barcelona, Spain
Antonio Martínez
Department of Pathology, Hospital Clinic de Barcelona, Barcelona, Spain
Patricia Galván
Translational Genomics and Targeted Therapies in Solid Tumors, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain
Yi-Hsuan Tsai
Reveal Genomics, Barcelona, Spain
Blanca González-Farré
Translational Genomics and Targeted Therapies in Solid Tumors, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain; Department of Pathology, Hospital Clinic de Barcelona, Barcelona, Spain
Aurea Mira
Centro de Diagnóstico Biomédico, Hospital Clinic, Barcelona, Spain
Ana Vivancos
Vall d´Hebron Institute of Oncology (VHIO), Barcelona, Spain
Patricia Villagrasa
Reveal Genomics, Barcelona, Spain
Joel S. Parker
Life Edit Therapeutics, North Carolina, USA
Pierfranco Conte
Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy; Medical Oncology 2, Istituto Oncologico Veneto, IRCCS, Padova, Italy
Charles M. Perou
Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, USA
Summary: Background: Both clinical and genomic data independently predict survival and treatment response in early-stage HER2-positive breast cancer. Here we present the development and validation of a new HER2DX risk score, and a new HER2DX pathological complete response (pCR) score, both based on a 27-gene expression plus clinical feature-based classifier. Methods: HER2DX is a supervised learning algorithm incorporating tumour size, nodal staging, and 4 gene expression signatures tracking immune infiltration, tumour cell proliferation, luminal differentiation, and the expression of the HER2 amplicon, into a single score. 434 HER2-positive tumours from the Short-HER trial were used to train a prognostic risk model; 268 cases from an independent cohort were used to verify the accuracy of the HER2DX risk score. In addition, 116 cases treated with neoadjuvant anti-HER2-based chemotherapy were used to train a predictive model of pathological complete response (pCR); two independent cohorts of 91 and 67 cases were used to verify the accuracy of the HER2DX pCR likelihood score. Five publicly available independent datasets with >1,000 patients with early-stage HER2-positive disease were also analysed. Findings: In Short-HER, HER2DX variables were associated with good risk outcomes (i.e., immune, and luminal) and poor risk outcomes (i.e., proliferation, and tumour and nodal staging). In an independent cohort, continuous HER2DX risk score was significantly associated with disease-free survival (DFS) (p=0·002); the 5-year DFS in the low-risk group was 97·4% (94·4-100·0%). For the neoadjuvant pCR predictor training cohort, HER2DX variables were associated with pCR (i.e., immune, proliferation and HER2 amplicon) and non-pCR (i.e., luminal, and tumour and nodal staging). In both independent test set cohorts, continuous HER2DX pCR likelihood score was significantly associated with pCR (p<0·0001). A weak negative correlation was found between the HER2DX risk score versus the pCR score (correlation coefficient -0·19). Interpretation: The two HER2DX tests provide accurate estimates of the risk of recurrence, and the likelihood to achieve a pCR, in early-stage HER2-positive breast cancer. Funding: This study received funding from Reveal Genomics, IDIBAPS and the University of Padova.