Tumor Intrinsic Subtypes and Gene Expression Signatures in Early-Stage ERBB2/HER2-Positive Breast Cancer: A Pooled Analysis of CALGB 40601, NeoALTTO, and NSABP B-41 Trials.

Autor:	Fernandez-Martinez A; Lineberger Comprehensive Center, University of North Carolina, Chapel Hill.; Department of Genetics, University of North Carolina, Chapel Hill., Rediti M; Breast Cancer Translational Research Laboratory, Institut Jules Bordet, Hôpital Universitaire de Bruxelles (H.U.B), Université Libre de Bruxelles (ULB), Brussels, Belgium., Tang G; NSABP Foundation Inc., Pittsburgh, Pennsylvania.; Department of Biostatistics, University of Pittsburgh, Pittsburgh, Pennsylvania., Pascual T; Lineberger Comprehensive Center, University of North Carolina, Chapel Hill.; Department of Medical Oncology, Hospital Clínic de Barcelona, Spain.; Translational Genomics and Targeted Therapeutics in Solid Tumors, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain.; SOLTI Breast Cancer Cooperative Group, Barcelona, Spain., Hoadley KA; Lineberger Comprehensive Center, University of North Carolina, Chapel Hill.; Department of Genetics, University of North Carolina, Chapel Hill., Venet D; Breast Cancer Translational Research Laboratory, Institut Jules Bordet, Hôpital Universitaire de Bruxelles (H.U.B), Université Libre de Bruxelles (ULB), Brussels, Belgium., Rashid NU; Department of Biostatistics, University of North Carolina, Chapel Hill., Spears PA; Lineberger Comprehensive Center, University of North Carolina, Chapel Hill., Islam MN; Genomics and Epigenomics Shared Resource (GESR), Georgetown University Medical Center, Washington, DC., El-Abed S; Breast International Group, Brussels, Belgium., Bliss J; The Institute of Cancer Research, Clinical Trials & Statistics Unit, London, United Kingdom., Lambertini M; Department of Internal Medicine and Medical Specialties (DiMI), School of Medicine, University of Genova, Genova, Italy.; Department of Medical Oncology, UOC Clinica di Oncologia Medica, IRCCS Ospedale Policlinico San Martino, Genova, Italy., Di Cosimo S; Integrated Biology Platform, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy., Huobe J; Kantonsspital St. Gallen, Brustzentrum, Departement Interdisziplinäre medizinische Dienste, St. Gallen, Switzerland., Goerlitz D; Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC., Hu R; Genomics and Epigenomics Shared Resource (GESR), Georgetown University Medical Center, Washington, DC., Lucas PC; NSABP Foundation Inc., Pittsburgh, Pennsylvania.; Department of Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania., Swain SM; NSABP Foundation Inc., Pittsburgh, Pennsylvania.; Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC., Sotiriou C; Breast Cancer Translational Research Laboratory, Institut Jules Bordet, Hôpital Universitaire de Bruxelles (H.U.B), Université Libre de Bruxelles (ULB), Brussels, Belgium., Perou CM; Lineberger Comprehensive Center, University of North Carolina, Chapel Hill.; Department of Genetics, University of North Carolina, Chapel Hill., Carey LA; Lineberger Comprehensive Center, University of North Carolina, Chapel Hill.; Division of Hematology-Oncology, Department of Medicine, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
Jazyk:	angličtina
Zdroj:	JAMA oncology [JAMA Oncol] 2024 May 01; Vol. 10 (5), pp. 603-611.
DOI:	10.1001/jamaoncol.2023.7304
Abstrakt:	Importance: Biologic features may affect pathologic complete response (pCR) and event-free survival (EFS) after neoadjuvant chemotherapy plus ERBB2/HER2 blockade in ERBB2/HER2-positive early breast cancer (EBC). Objective: To define the quantitative association between pCR and EFS by intrinsic subtype and by other gene expression signatures in a pooled analysis of 3 phase 3 trials: CALGB 40601, NeoALTTO, and NSABP B-41. Design, Setting, and Participants: In this retrospective pooled analysis, 1289 patients with EBC received chemotherapy plus either trastuzumab, lapatinib, or the combination, with a combined median follow-up of 5.5 years. Gene expression profiling by RNA sequencing was obtained from 758 samples, and intrinsic subtypes and 618 gene expression signatures were calculated. Data analyses were performed from June 1, 2020, to January 1, 2023. Main Outcomes and Measures: The association of clinical variables and gene expression biomarkers with pCR and EFS were studied by logistic regression and Cox analyses. Results: In the pooled analysis, of 758 women, median age was 49 years, 12% were Asian, 6% Black, and 75% were White. Overall, pCR results were associated with EFS in the ERBB2-enriched (hazard ratio [HR], 0.45; 95% CI, 0.29-0.70; P < .001) and basal-like (HR, 0.19; 95% CI, 0.04-0.86; P = .03) subtypes but not in luminal A or B tumors. Dual trastuzumab plus lapatinib blockade over trastuzumab alone had a trend toward EFS benefit in the intention-to-treat population; however, in the ERBB2-enriched subtype there was a significant and independent EFS benefit of trastuzumab plus lapatinib vs trastuzumab alone (HR, 0.47; 95% CI, 0.27-0.83; P = .009). Overall, 275 of 618 gene expression signatures (44.5%) were significantly associated with pCR and 9 of 618 (1.5%) with EFS. The ERBB2/HER2 amplicon and multiple immune signatures were significantly associated with pCR. Luminal-related signatures were associated with lower pCR rates but better EFS, especially among patients with residual disease and independent of hormone receptor status. There was significant adjusted HR for pCR ranging from 0.45 to 0.81 (higher pCR) and 1.21-1.94 (lower pCR rate); significant adjusted HR for EFS ranged from 0.71 to 0.94. Conclusions and Relevance: In patients with ERBB2/HER2-positive EBC, the association between pCR and EFS differed by tumor intrinsic subtype, and the benefit of dual ERBB2/HER2 blockade was limited to ERBB2-enriched tumors. Immune-activated signatures were concordantly associated with higher pCR rates and better EFS, whereas luminal signatures were associated with lower pCR rates.
Databáze:	MEDLINE
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