{"doi":"10.17615/hpvv-f686","title":"A multivariable prognostic score to guide systemic therapy in early-stage HER2-positive breast cancer: a retrospective study with an external evaluation","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 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 Inst","journal":"UNC Libraries","year":2021,"id":229743,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9114,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":303797,"name":"Enrico Tagliafico","orcid":"0000-0003-0981-2542","position":1,"is_corresponding":false},{"id":755398,"name":"V. Guarneri","orcid":null,"position":2,"is_corresponding":false},{"id":755416,"name":"G. Griguolo","orcid":null,"position":3,"is_corresponding":false},{"id":460167,"name":"B. Adamo","orcid":null,"position":4,"is_corresponding":false},{"id":303786,"name":"Antonino Musolino","orcid":"0000-0002-7979-6261","position":5,"is_corresponding":false},{"id":834723,"name":"E. Sanfeliu","orcid":null,"position":6,"is_corresponding":false},{"id":834724,"name":"J.M. Cejalvo","orcid":null,"position":7,"is_corresponding":false},{"id":755401,"name":"N. Chic","orcid":null,"position":8,"is_corresponding":false},{"id":541477,"name":"C.M. Perou","orcid":null,"position":9,"is_corresponding":false},{"id":834725,"name":"L. Urso","orcid":null,"position":10,"is_corresponding":false},{"id":834726,"name":"R. López","orcid":null,"position":11,"is_corresponding":false},{"id":167726,"name":"B. Conte","orcid":null,"position":12,"is_corresponding":false},{"id":431151,"name":"M. Oliveira","orcid":null,"position":13,"is_corresponding":false},{"id":834727,"name":"F. Miglietta","orcid":null,"position":14,"is_corresponding":false},{"id":834728,"name":"L. Paré","orcid":null,"position":15,"is_corresponding":false},{"id":834729,"name":"E. Ciruelos","orcid":null,"position":16,"is_corresponding":false},{"id":834730,"name":"J. Alarcón","orcid":null,"position":17,"is_corresponding":false},{"id":303795,"name":"Federico Piacentini","orcid":"0000-0001-8969-638X","position":18,"is_corresponding":false},{"id":755417,"name":"S. Pernas","orcid":null,"position":19,"is_corresponding":false},{"id":755408,"name":"T. Pascual","orcid":null,"position":20,"is_corresponding":false},{"id":755407,"name":"L.A. Carey","orcid":null,"position":21,"is_corresponding":false},{"id":591286,"name":"J.S. Parker","orcid":null,"position":22,"is_corresponding":false},{"id":834731,"name":"A.A. Brandes","orcid":null,"position":23,"is_corresponding":false},{"id":427041,"name":"A. Prat","orcid":null,"position":24,"is_corresponding":false},{"id":755418,"name":"F. Brasó-Maristany","orcid":null,"position":25,"is_corresponding":false},{"id":457766,"name":"M. Vidal","orcid":null,"position":26,"is_corresponding":false},{"id":306087,"name":"Antonio Frassoldati","orcid":null,"position":27,"is_corresponding":false},{"id":755406,"name":"P. Villagrasa","orcid":null,"position":28,"is_corresponding":false},{"id":303781,"name":"Giancarlo Bisagni","orcid":"0000-0003-1042-3771","position":29,"is_corresponding":false},{"id":834732,"name":"C. Saura","orcid":null,"position":30,"is_corresponding":false},{"id":834733,"name":"A Llombart-Cussac","orcid":null,"position":31,"is_corresponding":false},{"id":834734,"name":"Roberto D apos Amico","orcid":null,"position":32,"is_corresponding":false},{"id":834735,"name":"L. Manso","orcid":null,"position":33,"is_corresponding":false},{"id":834736,"name":"M.V. Dieci","orcid":null,"position":34,"is_corresponding":false},{"id":834737,"name":"P. Conte","orcid":null,"position":35,"is_corresponding":false},{"id":834738,"name":"B. González-Farré","orcid":null,"position":36,"is_corresponding":false},{"id":755402,"name":"F. Schettini","orcid":null,"position":37,"is_corresponding":false},{"id":755415,"name":"M. Muñoz","orcid":null,"position":38,"is_corresponding":false},{"id":834722,"name":"J. Cortés","orcid":null,"position":0,"is_corresponding":true}],"reference_count":0,"raw_metadata":null,"created_at":"2026-07-18T23:55:01.675482Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}