Aleix Prat1, Valentina Guarneri2, Laia Paré3, Gaia Griguolo2, Tomás Pascual4, Maria V Dieci2, Núria Chic5, Blanca González-Farré6, Antonio Frassoldati7, Esther Sanfeliu6, Juan M Cejalvo8, Montserrat Muñoz5, Giancarlo Bisagni9, Fara Brasó-Maristany10, Loredana Urso11, Maria Vidal5, Alba A Brandes12, Barbara Adamo5, Antonino Musolino13, Federica Miglietta2, Benedetta Conte14, Mafalda Oliveira15, Cristina Saura15, Sònia Pernas16, Jesús Alarcón17, Antonio Llombart-Cussac18, Javier Cortés19, Luis Manso20, Rafael López21, Eva Ciruelos20, Francesco Schettini22, Patricia Villagrasa3, Lisa A Carey23, Charles M Perou23, Federico Piacentini24, Roberto D'Amico25, Enrico Tagliafico25, Joel S Parker23, Pierfranco Conte26. 1. SOLTI Breast Cancer Research Group, Barcelona, Spain; Department of Medical Oncology, Hospital Clinic of Barcelona, Barcelona, Spain; Translational Genomics and Targeted Therapeutics in Solid Tumors, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain; Department of Medicine, University of Barcelona, Barcelona, Spain. Electronic address: alprat@clinic.cat. 2. Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy; Medical Oncology 2, Istituto Oncologico Veneto, IRCCS, Padova, Italy. 3. SOLTI Breast Cancer Research Group, Barcelona, Spain. 4. SOLTI Breast Cancer Research Group, Barcelona, Spain; Translational Genomics and Targeted Therapeutics in Solid Tumors, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain; Lineberger Comprehensive Cancer Center, Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. 5. SOLTI Breast Cancer Research Group, Barcelona, Spain; Department of Medical Oncology, Hospital Clinic of Barcelona, Barcelona, Spain; Translational Genomics and Targeted Therapeutics in Solid Tumors, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain. 6. SOLTI Breast Cancer Research Group, Barcelona, Spain; Translational Genomics and Targeted Therapeutics in Solid Tumors, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain; Department of Pathology, Hospital Clinic of Barcelona, Barcelona, Spain. 7. Clinical Oncology, Department of Morphology, Surgery and Experimental Medicine, S Anna University Hospital, Ferrara, Italy. 8. Department of Medical Oncology, Hospital Clínico Universitario of Valencia, Valencia, Spain. 9. Pathology Unit, Azienda Unità Sanitaria Locale-IRCCS di Reggio Emilia, Reggio Emilia, Emilia-Romagna, Italy. 10. SOLTI Breast Cancer Research Group, Barcelona, Spain; Translational Genomics and Targeted Therapeutics in Solid Tumors, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain. 11. Medical Oncology 2, Istituto Oncologico Veneto, IRCCS, Padova, Italy. 12. Medical Oncology, Azienda Unità Sanitaria Locale di Bologna-IRCCS Istituto delle Scienze Neurologiche, Bologna. 13. Department of Medicine and Surgery, and the Medical Oncology and Breast Unit, University Hospital of Parma, Piacenza, Italy. 14. Translational Genomics and Targeted Therapeutics in Solid Tumors, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain. 15. SOLTI Breast Cancer Research Group, Barcelona, Spain; Department of Medical Oncology, Vall d'Hebron University Hospital; Vall d'Hebron Institute of Oncology, Barcelona, Spain. 16. SOLTI Breast Cancer Research Group, Barcelona, Spain; Department of Medical Oncology, Institut Català d'Oncologia Hospitalet, Hospitalet de Llobregat, Spain. 17. SOLTI Breast Cancer Research Group, Barcelona, Spain; Hospital Universitario Son Espases, Carretera de Valldemossa, Palma de Mallorca, Spain. 18. Department of Medical Oncology, Hospital Arnau de Vilanova, Valencia, Spain. 19. Department of Medical Oncology, Vall d'Hebron University Hospital; Vall d'Hebron Institute of Oncology, Barcelona, Spain; IOB Institute of Oncology, Quiron Group, Barcelona, Spain. 20. SOLTI Breast Cancer Research Group, Barcelona, Spain; Department of Medical Oncology, Hospital 12 de Octubre, Madrid, Spain. 21. SOLTI Breast Cancer Research Group, Barcelona, Spain; Department of Medical Oncology, Complejo Universitario de Santiago de Compostela-CIBERONC, Santiago de Compostela, Spain. 22. SOLTI Breast Cancer Research Group, Barcelona, Spain; Translational Genomics and Targeted Therapeutics in Solid Tumors, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain; Department of Medical Oncology, University of Naples Federico II, Naples, Italy. 23. Lineberger Comprehensive Cancer Center, Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. 24. Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy. 25. Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy; Center for Genome Research, University of Modena and Reggio Emilia, Modena, Italy. 26. Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy; Medical Oncology 2, Istituto Oncologico Veneto, IRCCS, Padova, Italy; Department of Medical Oncology UO Oncologia Medica 2, IRCCS Ospedale Policlinico San Martino, Genova, Italy.
Abstract
BACKGROUND: In early-stage HER2-positive breast cancer, escalation or de-escalation of systemic therapy is a controversial topic. As an aid to treatment decisions, we aimed to develop a prognostic assay that integrates multiple data types for predicting survival outcome in patients with newly diagnosed HER2-positive breast cancer. METHODS: We derived a combined prognostic model using retrospective clinical-pathological data on stromal tumour-infiltrating lymphocytes, PAM50 subtypes, and expression of 55 genes obtained from patients who participated in the Short-HER phase 3 trial. The trial enrolled patients with newly diagnosed, node-positive, HER2-positive breast cancer or, if node negative, with at least one risk factor (ie, tumour size >2 cm, histological grade 3, lymphovascular invasion, Ki67 >20%, age ≤35 years, or hormone receptor negativity), and randomly assigned them to adjuvant anthracycline plus taxane-based combinations with either 9 weeks or 1 year of trastuzumab. Trastuzumab was administered intravenously every 3 weeks (8 mg/kg loading dose at first cycle, and 6 mg/kg thereafter) for 18 doses or weekly (4 mg/kg loading dose in the first week, and 2 mg/kg thereafter) for 9 weeks, starting concomitantly with the first taxane dose. Median follow-up was 91·4 months (IQR 75·1-105·6). The primary objective of our study was to derive and evaluate a combined prognostic score associated with distant metastasis-free survival (the time between randomisation and distant recurrence or death before recurrence), an exploratory endpoint in Short-HER. Patient samples in the training dataset were split into a training set (n=290) and a testing set (n=145), balancing for event and treatment group. The training set was further stratified into 100 iterations of Monte-Carlo cross validation (MCCV). Cox proportional hazard models were fit to MCCV training samples using Elastic-Net. A maximum of 92 features were assessed. The final prognostic model was evaluated in an independent combined dataset of 267 patients with early-stage HER2-positive breast cancer treated with differentneoadjuvant and adjuvant anti-HER2-based combinations and from four other studies (PAMELA, CHER-LOB, Hospital Clinic, and Padova) with disease-free survival outcome data. FINDINGS: From Short-HER, data from 435 (35%) of 1254 patients for tumour size (T1 vs rest), nodal status (N0 vs rest), number of tumour-infiltrating lymphocytes (continuous variable), subtype (HER2-enriched and basal-like vs rest), and 13 genes composed the final model (named HER2DX). HER2DX was significantly associated with distant metastasis-free survival as a continuous variable (p<0·0001). HER2DX median score for quartiles 1-2 was identified as the cutoff to identify low-risk patients; and the score that distinguished quartile 3 from quartile 4 was the cutoff to distinguish medium-risk and high-risk populations. The 5-year distant metastasis-free survival of the low-risk, medium-risk, and high-risk populations were 98·1% (95% CI 96·3-99·9), 88·9% (83·2-95·0), and 73·9% (66·0-82·7), respectively (low-risk vs high-risk hazard ratio [HR] 0·04, 95% CI 0·0-0·1, p<0·0001). In the evaluation cohort, HER2DX was significantly associated with disease-free survival as a continuous variable (HR 2·77, 95% CI 1·4-5·6, p=0·0040) and as group categories (low-risk vs high-risk HR 0·27, 0·1-0·7, p=0·005). 5-year disease-free survival in the HER2DX low-risk group was 93·5% (89·0-98·3%) and in the high-risk group was 81·1% (71·5-92·1). INTERPRETATION: The HER2DX combined prognostic score identifies patients with early-stage, HER2-positive breast cancer who might be candidates for escalated or de-escalated systemic treatment. Future clinical validation of HER2DX seems warranted to establish its use in different scenarios, especially in the neoadjuvant setting. FUNDING: Instituto Salud Carlos III, Save the Mama, Pas a Pas, Fundación Científica, Asociación Española Contra el Cáncer, Fundación SEOM, National Institutes of Health, Agenzia Italiana del Farmaco, International Agency for Research on Cancer, and the Veneto Institute of Oncology, and Italian Association for Cancer Research.
RCT Entities:
BACKGROUND: In early-stage HER2-positive breast cancer, escalation or de-escalation of systemic therapy is a controversial topic. As an aid to treatment decisions, we aimed to develop a prognostic assay that integrates multiple data types for predicting survival outcome in patients with newly diagnosed HER2-positive breast cancer. METHODS: We derived a combined prognostic model using retrospective clinical-pathological data on stromal tumour-infiltrating lymphocytes, PAM50 subtypes, and expression of 55 genes obtained from patients who participated in the Short-HER phase 3 trial. The trial enrolled patients with newly diagnosed, node-positive, HER2-positive breast cancer or, if node negative, with at least one risk factor (ie, tumour size >2 cm, histological grade 3, lymphovascular invasion, Ki67 >20%, age ≤35 years, or hormone receptor negativity), and randomly assigned them to adjuvant anthracycline plus taxane-based combinations with either 9 weeks or 1 year of trastuzumab. Trastuzumab was administered intravenously every 3 weeks (8 mg/kg loading dose at first cycle, and 6 mg/kg thereafter) for 18 doses or weekly (4 mg/kg loading dose in the first week, and 2 mg/kg thereafter) for 9 weeks, starting concomitantly with the first taxane dose. Median follow-up was 91·4 months (IQR 75·1-105·6). The primary objective of our study was to derive and evaluate a combined prognostic score associated with distant metastasis-free survival (the time between randomisation and distant recurrence or death before recurrence), an exploratory endpoint in Short-HER. Patient samples in the training dataset were split into a training set (n=290) and a testing set (n=145), balancing for event and treatment group. The training set was further stratified into 100 iterations of Monte-Carlo cross validation (MCCV). Cox proportional hazard models were fit to MCCV training samples using Elastic-Net. A maximum of 92 features were assessed. The final prognostic model was evaluated in an independent combined dataset of 267 patients with early-stage HER2-positive breast cancer treated with different neoadjuvant and adjuvant anti-HER2-based combinations and from four other studies (PAMELA, CHER-LOB, Hospital Clinic, and Padova) with disease-free survival outcome data. FINDINGS: From Short-HER, data from 435 (35%) of 1254 patients for tumour size (T1 vs rest), nodal status (N0 vs rest), number of tumour-infiltrating lymphocytes (continuous variable), subtype (HER2-enriched and basal-like vs rest), and 13 genes composed the final model (named HER2DX). HER2DX was significantly associated with distant metastasis-free survival as a continuous variable (p<0·0001). HER2DX median score for quartiles 1-2 was identified as the cutoff to identify low-risk patients; and the score that distinguished quartile 3 from quartile 4 was the cutoff to distinguish medium-risk and high-risk populations. The 5-year distant metastasis-free survival of the low-risk, medium-risk, and high-risk populations were 98·1% (95% CI 96·3-99·9), 88·9% (83·2-95·0), and 73·9% (66·0-82·7), respectively (low-risk vs high-risk hazard ratio [HR] 0·04, 95% CI 0·0-0·1, p<0·0001). In the evaluation cohort, HER2DX was significantly associated with disease-free survival as a continuous variable (HR 2·77, 95% CI 1·4-5·6, p=0·0040) and as group categories (low-risk vs high-risk HR 0·27, 0·1-0·7, p=0·005). 5-year disease-free survival in the HER2DX low-risk group was 93·5% (89·0-98·3%) and in the high-risk group was 81·1% (71·5-92·1). INTERPRETATION: The HER2DX combined prognostic score identifies patients with early-stage, HER2-positive breast cancer who might be candidates for escalated or de-escalated systemic treatment. Future clinical validation of HER2DX seems warranted to establish its use in different scenarios, especially in the neoadjuvant setting. FUNDING: Instituto Salud Carlos III, Save the Mama, Pas a Pas, Fundación Científica, Asociación Española Contra el Cáncer, Fundación SEOM, National Institutes of Health, Agenzia Italiana del Farmaco, International Agency for Research on Cancer, and the Veneto Institute of Oncology, and Italian Association for Cancer Research.
Authors: P Conte; A Frassoldati; G Bisagni; A A Brandes; M Donadio; O Garrone; F Piacentini; L Cavanna; F Giotta; M Aieta; V Gebbia; A Molino; A Musolino; A Ferro; R Maltoni; S Danese; C Zamagni; A Rimanti; K Cagossi; A Russo; P Pronzato; F Giovanardi; G Moretti; L Lombardo; A Schirone; A Beano; L Amaducci; E A Bajardi; R Vicini; S Balduzzi; R D'Amico; V Guarneri Journal: Ann Oncol Date: 2018-12-01 Impact factor: 32.976
Authors: Roberto Salgado; Carsten Denkert; Christine Campbell; Peter Savas; Paolo Nuciforo; Paolo Nucifero; Claudia Aura; Evandro de Azambuja; Holger Eidtmann; Catherine E Ellis; Jose Baselga; Martine J Piccart-Gebhart; Stefan Michiels; Ian Bradbury; Christos Sotiriou; Sherene Loi Journal: JAMA Oncol Date: 2015-07 Impact factor: 31.777
Authors: Miguel Martin; Frankie A Holmes; Bent Ejlertsen; Suzette Delaloge; Beverly Moy; Hiroji Iwata; Gunter von Minckwitz; Stephen K L Chia; Janine Mansi; Carlos H Barrios; Michael Gnant; Zorica Tomašević; Neelima Denduluri; Robert Šeparović; Erhan Gokmen; Anna Bashford; Manuel Ruiz Borrego; Sung-Bae Kim; Erik Hugger Jakobsen; Audrone Ciceniene; Kenichi Inoue; Friedrich Overkamp; Joan B Heijns; Anne C Armstrong; John S Link; Anil Abraham Joy; Richard Bryce; Alvin Wong; Susan Moran; Bin Yao; Feng Xu; Alan Auerbach; Marc Buyse; Arlene Chan Journal: Lancet Oncol Date: 2017-11-13 Impact factor: 41.316
Authors: M V Dieci; A Prat; E Tagliafico; L Paré; G Ficarra; G Bisagni; F Piacentini; D G Generali; P Conte; V Guarneri Journal: Ann Oncol Date: 2016-08-02 Impact factor: 32.976
Authors: Edith A Perez; Edward H Romond; Vera J Suman; Jong-Hyeon Jeong; George Sledge; Charles E Geyer; Silvana Martino; Priya Rastogi; Julie Gralow; Sandra M Swain; Eric P Winer; Gerardo Colon-Otero; Nancy E Davidson; Eleftherios Mamounas; Jo Anne Zujewski; Norman Wolmark Journal: J Clin Oncol Date: 2014-10-20 Impact factor: 44.544
Authors: S Loibl; I Majewski; V Guarneri; V Nekljudova; E Holmes; E Bria; C Denkert; C Schem; C Sotiriou; S Loi; M Untch; P Conte; R Bernards; M Piccart; G von Minckwitz; J Baselga Journal: Ann Oncol Date: 2016-05-13 Impact factor: 32.976
Authors: Mariana Brandão; Rafael Caparica; Luca Malorni; Aleix Prat; Lisa A Carey; Martine Piccart Journal: Clin Cancer Res Date: 2020-02-11 Impact factor: 12.531
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Authors: Po-Hung Hsieh; Alec J Kacew; Marie Dreyer; Anthony V Serritella; Randall W Knoebel; Garth W Strohbehn; Mark J Ratain Journal: NPJ Breast Cancer Date: 2022-03-14