Development and validation of a prognostic 15-gene signature for stratifying HER2+/ER+ breast cancer.

{"sci_version": "1.2", "schema": "https://corpus.bntrg.co.uk/sci/1.0/sci.schema.json", "id": "pmid:37216014", "kind": "science-record", "revision": 3, "content_hash": "sha256:e0537dae9553d1ffcbdb8072b7f4cd1e37f2d8f4a5fd29bdf3d19dfa6ec727fb", "created_at": "2026-11-01T19:01:55Z", "updated_at": "2026-11-01T22:09:32Z", "generator": {"name": "corpus-assay-engine", "run_id": "reading-sci-2026-11-01"}, "paper": {"state": "complete", "title": "Development and validation of a prognostic 15-gene signature for stratifying HER2+/ER+ breast cancer.", "doi": "10.1016/j.csbj.2023.05.002", "pmid": "37216014", "authors": ["Qian Liu", "Shujun Huang", "Danielle Desautels", "Kirk J McManus", "Leigh Murphy", "Pingzhao Hu"], "journal": "Computational and structural biotechnology journal", "year": 2023, "abstract": "Background: Human epidermal growth receptor 2-positive (HER2+) breast cancer (BC) is a heterogeneous subgroup. Estrogen receptor (ER) status is emerging as a predictive marker within HER2+ BCs, with the HER2+/ER+ cases usually having better survival in the first 5 years after diagnosis but have higher recurrence risk after 5 years compared to HER2+/ER-. This is possibly because sustained ER signaling in HER2+ BCs helps escape the HER2 blockade. Currently HER2+/ER+ BC is understudied and lacks biomarkers. Thus, a better understanding of the underlying molecular diversity is important to find new therapy targets for HER2+/ER+ BCs.\nMethods: In this study, we performed unsupervised consensus clustering together with genome-wide Cox regression analyses on the gene expression data of 123 HER2+/ER+ BC from The Cancer Genome Atlas Breast Invasive Carcinoma (TCGA-BRCA) cohort to identify distinct HER2+/ER+ subgroups. A supervised eXtreme Gradient Boosting (XGBoost) classifier was then built in TCGA using the identified subgroups and validated in another two independent datasets (Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) and Gene Expression Omnibus (GEO) (accession number GSE149283)). Computational characterization analyses were also performed on the predicted subgroups in different HER2+/ER+ BC cohorts.\nResults: We identified two distinct HER2+/ER+ subgroups with different survival outcomes using the expression profiles of 549 survival-associated genes from the Cox regression analyses. Genome-wide gene expression differential analyses found 197 differentially expressed genes between the two identified subgroups, with 15 genes overlapping the 549 survival-associated genes.XGBoost classifier, using the expression values of the 15 genes, achieved a strong cross-validated performance (Area under the curve (AUC) = 0.85, Sensitivity = 0.76, specificity = 0.77) in predicting the subgroup labels. Further investigation partially confirmed the differences in survival, drug response, tumor-infiltrating lymphocytes, published gene signatures, and CRISPR-Cas9 knockout screened gene dependency scores between the two identified subgroups.\nConclusion: This is the first study to stratify HER2+/ER+ tumors. Overall, the initial results from different cohorts showed there exist two distinct subgroups in HER2+/ER+ tumors, which can be distinguished by a 15-gene signature. Our findings could potentially guide the development of future precision therapies targeted on HER2+/ER+ BC.", "claims": [{"id": "claim-method", "statement": "In this study, we performed unsupervised consensus clustering together with genome-wide Cox regression analyses on the gene expression data of 123 HER2+/ER+ BC from The Cancer Genome Atlas Breast Invasive Carcinoma (TCGA-BRCA) cohort to identify distinct HER2+/ER+ subgroups.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:37216014", "locator": "sections[0] \"Abstract\" paragraph 2", "quote": "In this study, we performed unsupervised consensus clustering together with genome-wide Cox regression analyses on the gene expression data of 123 HER2+/ER+ BC from The Cancer Genome Atlas Breast Invasive Carcinoma (TCGA-BRCA) cohort to identify distinct HER2+/ER+ subgroups."}], "state": "complete"}, {"id": "claim-data-access", "statement": "The raw read counts of RNA-sequencing data and clinical information of The Cancer Genome Atlas Breast Invasive Carcinoma (TCGA-BRCA) cohort [22] were downloaded through R package “TCGAbiolinks” [23]. TCGA-BRCA has 1102 patients, with each having more than 55,368 gene expression values. After filtering for the patients showing ER+ and HER2+ by immunohistochemistry (IHC), there are a total of 123 HER2+/ER+ BC patients. TCGA also provides the gene expression data of 113 normal adjacent breast tissue samples.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:37216014", "locator": "sections[3] \"Data sources\" paragraph 2", "quote": "The raw read counts of RNA-sequencing data and clinical information of The Cancer Genome Atlas Breast Invasive Carcinoma (TCGA-BRCA) cohort [22] were downloaded through R package “TCGAbiolinks” [23]. TCGA-BRCA has 1102 patients, with each having more than 55,368 gene expression values. After filtering for the patients showing ER+ and HER2+ by immunohistochemistry (IHC), there are a total of 123 HER2+/ER+ BC patients. TCGA also provides the gene expression data of 113 normal adjacent breast tissue samples."}], "state": "complete"}, {"id": "claim-target-result", "statement": "Using unsupervised consensus clustering and genome-wide Cox regression analyses of gene-expression data from 123 HER2+/ER+ TCGA-BRCA cases, the study identified two distinct subgroups distinguishable by a 15-gene signature.", "kind": "qualitative", "target": null, "evidence": [{"asset": "source:pmid:37216014", "locator": "sections[0] \"Abstract\" paragraph 2", "quote": "In this study, we performed unsupervised consensus clustering together with genome-wide Cox regression analyses on the gene expression data of 123 HER2+/ER+ BC from The Cancer Genome Atlas Breast Invasive Carcinoma (TCGA-BRCA) cohort to identify distinct HER2+/ER+ subgroups."}, {"asset": "source:pmid:37216014", "locator": "sections[0] \"Abstract\" paragraph 3", "quote": "We identified two distinct HER2+/ER+ subgroups with different survival outcomes using the expression profiles of 549 survival-associated genes from the Cox regression analyses."}, {"asset": "source:pmid:37216014", "locator": "sections[0] \"Abstract\" paragraph 5", "quote": "Overall, the initial results from different cohorts showed there exist two distinct subgroups in HER2+/ER+ tumors, which can be distinguished by a 15-gene signature."}], "state": "complete"}], "gaps": []}, "experiment": {"state": "complete", "objective": "Using unsupervised consensus clustering and genome-wide Cox regression analyses of gene-expression data from 123 HER2+/ER+ TCGA-BRCA cases, the study identified two distinct subgroups distinguishable by a 15-gene signature.", "steps": [{"id": "read_published_estimate", "order": 1, "name": "Read the published estimate from the source", "kind": "other", "state": "complete", "blocked_on": null, "description": "The claim, method and evidence span published with the source article.", "duration_hours": null, "parameters": {}, "inputs": ["source:pmid:37216014"], "outputs": ["the published estimate and its evidence"], "instruments": [], "reagents": []}, {"id": "obtain_source_data", "order": 2, "name": "Obtain the source data from the named repository", "kind": "data-preparation", "state": "complete", "blocked_on": null, "description": "The GEO series accession resolves and its sample accessions are listed. This lane did not download the dataset or read its licence.", "duration_hours": null, "parameters": {}, "inputs": ["data:geo:GSE149283"], "outputs": ["the source data with its repository provenance"], "instruments": [], "reagents": []}, {"id": "run_analysis", "order": 3, "name": "Run the published analysis", "kind": "analysis", "state": "complete", "blocked_on": null, "description": "Apply the paper's statistical method to the resolved series and compare the result with the published target.", "duration_hours": null, "parameters": {}, "inputs": ["data:geo:GSE149283"], "outputs": ["the replicated result and its comparison"], "instruments": [], "reagents": []}], "materials": [], "instruments": [], "reagents": [], "conditions": {}, "gaps": []}, "data": {"state": "partial", "assets": [{"id": "source:pmid:37216014", "role": "manuscript", "format": "xml", "media_type": "application/xml", "uri": "https://doi.org/10.1016/j.csbj.2023.05.002", "sha256": "sha256:e273d394c9303aced7023bd8c3ba7c48d125c492b22633c3153e36111530af3f", "bytes": 50264, "access": "open", "state": "resolved", "reader": null, "reader_status": "reader_required", "identifier": "10.1016/j.csbj.2023.05.002", "version": null, "note": "Full article fetched from PMC; the checksum covers the rendered section body, not the original XML bytes.", "structure": {"pmcid": "PMC10196919", "source": "europe_pmc_fulltext", "coverage": "whole_body", "text_hash_scope": "rendered_section_body"}}, {"id": "data:geo:GSE149283", "role": "raw", "format": "geo-series", "media_type": "application/vnd.ncbi.geo-series+json", "uri": "https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE149283", "sha256": null, "bytes": null, "access": "open", "state": "resolved", "reader": null, "reader_status": "reader_required", "identifier": "GSE149283", "version": null, "note": "The raw read counts of RNA-sequencing data and clinical information of The Cancer Genome Atlas Breast Invasive Carcinoma (TCGA-BRCA) cohort [22] were downloaded through R package “TCGAbiolinks” [23]. TCGA-BRCA has 1102 patients, with each having more than 55,368 gene expression values. After filtering for the patients showing ER+ and HER2+ by immunohistochemistry (IHC), there are a total of 123 HER2+/ER+ BC patients. TCGA also provides the gene expression data of 113 normal adjacent breast tissue samples.", "structure": {"repository": "GEO", "access_route": "GEO accession URL", "access_statement_verbatim": "The raw read counts of RNA-sequencing data and clinical information of The Cancer Genome Atlas Breast Invasive Carcinoma (TCGA-BRCA) cohort [22] were downloaded through R package “TCGAbiolinks” [23]. TCGA-BRCA has 1102 patients, with each having more than 55,368 gene expression values. After filtering for the patients showing ER+ and HER2+ by immunohistochemistry (IHC), there are a total of 123 HER2+/ER+ BC patients. TCGA also provides the gene expression data of 113 normal adjacent breast tissue samples.", "access_statement_kind": "repository_route_statement", "sample_accessions": ["GSM4495524", "GSM4495525", "GSM4495526", "GSM4495527", "GSM4495528", "GSM4495529", "GSM4495530", "GSM4495531", "GSM4495532", "GSM4495533", "GSM4495534", "GSM4495535", "GSM4495536", "GSM4495537", "GSM4495538", "GSM4495539", "GSM4495540", "GSM4495541"], "sample_count": 18, "group_sizes": null, "group_sizes_basis": null, "platform": "23159", "taxon": "Homo sapiens", "title": "Gene expression profiling of primary HER2-positive breast cancers treated with neoadjuvant trastuzumab", "resolution_checked_at": "2026-11-01T18:46:34Z", "resolution_check": "identifier_resolution_only_no_download_no_licence_read", "downloaded": false, "licence_read": false}}], "gaps": ["asset:data:geo:GSE149283 not downloaded", "asset:data:geo:GSE149283 licence not read"]}, "analysis": {"state": "complete", "methods": [{"id": "method-1", "family": "survival_analysis", "specific": "cox_proportional_hazards", "label": "Survival analysis", "dsl_operations": ["cox_ph"], "missing_operations": [], "expressible": true, "parameters": {}, "data_shapes": ["time_to_event_with_censoring"], "evidence": {"score": 1.0, "band": "verbatim", "quote": "In this study, we performed unsupervised consensus clustering together with genome-wide Cox regression analyses on the gene expression data of 123 HER2+/ER+ BC from The Cancer Genome Atlas Breast Invasive Carcinoma (TCGA-BRCA) cohort to identify distinct HER2+/ER+ subgroups."}}, {"id": "method-2", "family": "machine_learning", "specific": "gradient_boosting", "label": "Machine learning", "dsl_operations": ["train_classifier", "cross_validate", "roc_auc"], "missing_operations": [], "expressible": true, "parameters": {}, "data_shapes": ["labelled_feature_matrix"], "evidence": {"score": 0.7, "band": "medium", "quote": "Gradient Boosting"}}], "targets": [], "gaps": []}, "capability": {"state": "complete", "requirements": [{"capability_id": "capability:computational_analysis", "label": "Computational analysis platform", "assay_families": ["meta_analysis", "machine_learning", "survival_analysis", "statistical_regression", "pca", "molecular_docking", "network_analysis", "differential_expression", "gwas"], "availability_state": "owned", "tier_unlocked": "R1", "candidate": "Automated Assays Laravel application and simulated adapters"}], "gaps": []}, "readiness": {"state": "complete", "tier": "R1", "blocking_axis": "none", "blocked_on": "nothing:replicable_now", "axes": {"method": {"tier": "R1", "expressible": true, "required_operations": ["cox_ph"], "missing_operations": [], "basis": "The paper names the method it used and the corpus's method extractor maps it onto the DSL catalogue: cox_proportional_hazards."}, "capability": {"tier": "R1", "capability_id": "capability:computational_analysis", "availability_state": "owned", "basis": "The computational analysis is owned. The physical bench the paper used is not, so a physical validation cannot be run here."}, "data": {"tier": "R1", "reachable": true, "accessions": ["GSE149283"], "resolved_accessions": ["GSE149283"], "statements": ["The raw read counts of RNA-sequencing data and clinical information of The Cancer Genome Atlas Breast Invasive Carcinoma (TCGA-BRCA) cohort [22] were downloaded through R package “TCGAbiolinks” [23]. TCGA-BRCA has 1102 patients, with each having more than 55,368 gene expression values. After filtering for the patients showing ER+ and HER2+ by immunohistochemistry (IHC), there are a total of 123 HER2+/ER+ BC patients. TCGA also provides the gene expression data of 113 normal adjacent breast tissue samples."], "basis": "The paper names GSE149283 in Gene Expression Omnibus (GEO) and the accession resolves in the repository. No dataset was downloaded and no licence was read."}}, "can_run": {"dsl_operations": ["cox_ph"], "assets": ["source:pmid:37216014", "data:geo:GSE149283"], "steps": ["run_analysis"]}, "must_build": {"dsl_operations": [], "converters": [], "readers": [], "capabilities": [], "data_gaps": ["data:geo:GSE149283"]}, "gaps": []}, "review": {"state": "partial", "machine_critique": {"kind": "extraction_review", "reader": {"model": "MiniMax-M3.1-Flash", "provider": "minimax", "provider_family": "minimax", "read_at": "2026-11-01T18:41:14Z", "independence": "single_reader"}, "evidence_check": {"method": "verbatim", "availability": null}, "calls": 5, "usage": {"prompt_tokens": 14499, "completion_tokens": 1879, "cached_tokens": 256}}, "human_critique": null, "stages": [{"id": "extraction", "state": "complete", "reader": "MiniMax-M3.1-Flash", "provider": "minimax"}], "gaps": ["review.independent_reader", "review.machine_critique", "review.human_critique"]}, "execution": {"state": "absent", "status": "not_run", "mode": null, "runs": [], "gaps": ["execution.not_run"]}, "provenance": {"entities": [{"id": "pmid:37216014", "type": "paper", "label": "pmid:37216014"}, {"id": "source:pmid:37216014", "type": "manuscript", "label": "PMID 37216014 full text"}, {"id": "data:geo:GSE149283", "type": "dataset", "label": "GEO GSE149283"}], "activities": [{"id": "activity-reading-sci-2026-11-01", "type": "classification", "used": [{"id": "pmid:37216014", "type": "paper", "label": "pmid:37216014"}, {"id": "source:pmid:37216014", "type": "manuscript", "label": "PMID 37216014 full text"}, {"id": "data:geo:GSE149283", "type": "dataset", "label": "GEO GSE149283"}], "agent": "agent:corpus-assay-engine"}, {"id": "activity-read-37216014", "type": "extraction", "used": ["source:pmid:37216014"], "agent": "agent:minimax-reader"}, {"id": "activity-resolve-GSE149283", "type": "accession_resolution", "used": ["data:geo:GSE149283"], "agent": "agent:corpus-assay-engine"}], "agents": [{"id": "agent:corpus-assay-engine", "type": "software", "label": "Corpus assay engine"}, {"id": "agent:minimax-reader", "type": "software", "label": "MiniMax literature reader"}], "source_run_id": "reading-sci-2026-11-01", "dsl_catalogue_fingerprint": "343fb30756ba6ec3", "capability_table_fingerprint": "2cb3e42f047d2ecf", "snapshot_id": "ba34b49490d9bfaf"}, "lineage": {"parent_id": "pmid:37216014", "parent_hash": "sha256:3e85705d0fa82d8d8d95bb0d6a38f91e7b6e953e290f02cc77f00a03bab5cd76", "fork_of": null, "generation": 2}, "gaps": ["asset:data:geo:GSE149283 licence not read", "asset:data:geo:GSE149283 not downloaded", "execution.not_run", "review.human_critique", "review.independent_reader", "review.machine_critique"], "assays": [{"role": "data_generation", "definition_id": "transfection", "definition_version": "99e1195c7d6f", "definition_digest": null, "required_operations": [], "support_state": "partial", "source_hashes": {"assay_lexicon": "99e1195c7d6f"}, "confidence": 0.85, "evidence": ["lymphocytes, published gene signatures, and CRISPR-Cas9 knockout screened gene dependency score"], "order_basis": "paper_text_order:2150", "id": "assay:1"}, {"role": "analysis", "definition_id": "survival_analysis", "definition_version": "f2132e96ae6c7a4e", "definition_digest": null, "required_operations": ["cox_ph"], "support_state": "supported", "source_hashes": {"dsl_catalogue": "f2132e96ae6c7a4e"}, "confidence": 1.0, "evidence": ["In this study, we performed unsupervised consensus clustering together with genome-wide Cox regression analyses on the gene expression data of 123 HER2+/ER+ BC from The Cancer Genome Atlas Breast Invasive Carcinoma (TCGA-BRCA) cohort to identify distinct HER2+/ER+ subgroups."], "order_basis": "consumes_earlier_output", "id": "assay:2"}]}