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. 2024 Apr:102:105043.
doi: 10.1016/j.ebiom.2024.105043. Epub 2024 Mar 5.

A 14-gene B-cell immune signature in early-stage triple-negative breast cancer (TNBC): a pooled analysis of seven studies

Benedetta Conte  1 , Fara Brasó-Maristany  2 , Adela Rodríguez Hernández  1 , Tomás Pascual  3 , Guillermo Villacampa  4 , Francesco Schettini  5 , Maria J Vidal Losada  6 , Elia Seguí  3 , Laura Angelats  1 , Isabel Garcia-Fructuoso  1 , Raquel Gómez-Bravo  1 , Natàlia Lorman-Carbó  7 , Laia Paré  8 , Mercedes Marín-Aguilera  8 , Olga Martínez-Sáez  1 , Barbara Adamo  1 , Esther Sanfeliu  9 , Beatrice Fratini  7 , Claudette Falato  10 , Núria Chic  1 , Ana Vivancos  11 , Patricia Villagrasa  8 , Johan Staaf  12 , Joel S Parker  13 , Charles M Perou  14 , Aleix Prat  15
Affiliations

A 14-gene B-cell immune signature in early-stage triple-negative breast cancer (TNBC): a pooled analysis of seven studies

Benedetta Conte et al. EBioMedicine. 2024 Apr.

Abstract

Background: Early-stage triple-negative breast cancer (TNBC) displays clinical and biological diversity. From a biological standpoint, immune infiltration plays a crucial role in TNBC prognosis. Currently, there is a lack of genomic tools aiding in treatment decisions for TNBC. This study aims to assess the effectiveness of a B-cell/immunoglobulin signature (IGG) alone, or in combination with tumor burden, in predicting prognosis and treatment response in patients with TNBC.

Methods: Genomic and clinical data were retrieved from 7 cohorts: SCAN-B (N = 874), BrighTNess (n = 482), CALGB-40603 (n = 389), METABRIC (n = 267), TCGA (n = 118), GSE58812 (n = 107), GSE21653 (n = 67). IGG and a risk score integrating IGG with tumor/nodal staging (IGG-Clin) were assessed for event-free survival (EFS) and overall survival (OS) in each cohort. Random effects model was used to derive pooled effect sizes. Association of IGG with pathological complete response (pCR) was assessed in CALGB-40603 and BrighTNess. Immune significance of IGG was estimated through CIBERSORTx and EcoTyper.

Findings: IGG was associated with improved EFS (pooled HR = 0.77, [95% CI = 0.70-0.85], I2 = 18%) and OS (pooled HR = 0.79, [0.73-0.85], I2 = 0%) across cohorts, and was predictive of pCR in CALGB-40603 (OR 1.25, [1.10-1.50]) and BrighTNess (OR 1.57 [1.25-1.98]). IGG-Clin was predictive of recurrence (pooled HR = 2.11, [1.75-2.55], I2 = 0%) and death (pooled HR = 1.99, 95% [0.84-4.73], I2 = 79%) across cohorts. IGG was associated with adaptive immune response at CIBERSORTx and EcoTyper analysis.

Interpretation: IGG is linked to improved prognosis and pCR in early-stage TNBC. The integration of IGG alongside tumor and nodal staging holds promise as an approach to identify patients benefitting from intensified or de-intensified treatments.

Funding: This study received funding from: Associació Beca Marta Santamaria, European Union's Horizon 2020 research and innovation and Marie Skłodowska-Curie Actions programs, Fundación FERO, Fundación CRIS contra el cáncer, Agència de Gestó d'Ajuts Universitaris i de Recerca, Instituto de Salud Carlos III, Fundación Contigo, Asociación Cáncer de Mama Metastásico IV, Breast Cancer Research Foundation, RESCUER, Fundación científica AECC and FSEOM.

Keywords: B-cell/immunoglobulin signature (IGG); Event-free survival (EFS); Gene expression; Overall survival (OS); Pathological complete response (pCR); Predictive biomarkers; Prognostic biomarkers; Triple-negative breast cancer (TNBC).

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Conflict of interest statement

Declaration of interests B. Conte reports speaker fees from Veracyte and payment for educational events from Medsite and Novartis. A. Prat reports consulting fees from Roche, Pfizer, Novartis, Amgen, BMS, Puma, Oncolytics Biotech, MSD, Guardant Health, Peptomyc and Lilly, lecture fees from Roche, Pfizer, Novartis, Amgen, BMS, Nanostring Technologies and Daiichi Sankyo; patents filed PCT/EP2016/080056, PCT/EP2022/086493, PCT/EP2023/060810, EP23382703 and EP23383369; stockholder and consultant of Reveal Genomics, SL; and institutional financial interests from Boehringer, Novartis, Roche, Nanostring, Sysmex Europa GmbH, Medica Scientia Innovation Research, SL, Celgene, Astellas and Pfizer. F. Schettini has declared consulting fees from Pfizer, honoraria for lectures from Novartis, Gilead and Daiichy Sankyo, and travel expenses from Novartis and Daiichy Sankyo. O. Martínez-Sáez has declared institutional grants from Roche; personal consulting fees from Roche and Reveal Genomics; honoraria for presentations by Daiichi Sankyo, Pierre Fabre, and Reveal Genomics; and travel expenses by Gilead, Pierre Fabre, Novartis, and MSD. A. Vivancos has declared institutional grants from Bristol Meyers Squibb, Incyte, and Roche; personal consulting fees from Bayer, Bristol Meyers Squibb (BMS); Guardant, Incyte, and Roche; and personal stock options from Reveal Genomics. F. Brasó-Maristany has patents filed: PCT/EP2022/086493, PCT/EP2023/060810, EP23382703 and EP23383369. J. Parker as declared individual and institutional royalties from Veracyte–Prosigna, consulting fees from Bristol Meyers Squibb, Reveal Genomics, and GeneCentric, and holds a patent for breast cancer subtyping. Additionally, he has an equity interest in Reveal Genomics. M. Vidal has declared honoraria for presentations from Novartis, Roche, Pfizer, and Daichii, and travel expenses from Roche and Pfizer. Additionally, she has participated on a Data Safety Monitoring Board or Advisory Board for Novartis and Roche. C. Perou has declared consulting fees and personal stock options from Reveal Genomics. T. Pascual has declared consulting fees from Novartis; honoraria from Novartis, Astra-zeneca, Veracyte, and Argenetics. I. Garcia-Fructuoso has declared honoraria for presentations from Novartis, Daiichi Sankyo, Esteve, GSK; and travel expenses from Novartis, Gilead, Daiichi Sankyo, Lilly, and BMS. L. Paré has declared contract from Reveal Genomics, a HER2DX patent filed (PCT/EP2022/086493), and the TNBCDX patent filed (EP23382703.9). M. Marín-Aguilera has declared contract from Reveal Genomics. P. Villagrasa has declared contract and personal stock options from Reveal Genomics, the HER2DX patent filed (PCT/EP2022/086493), and the DNADX patent filed (EP22382387.3). G. Villacampa has received a speaker's fee from Merck Sharp & Dohme, Pfizer, GlaxoSmithKline and Pierre Fabrer, and received consultant fees from Reveal Genomics. C. Falato is currently employed in AstraZeneca. The remaining authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Overview of the various patient cohorts assessed.
Fig. 2
Fig. 2
Kaplan–Meier estimates in node-negative or stage 1 TNBC according to the expression of the IGG signature (quartiles). (a) EFS in patients with node-negative disease; (b) OS in patients with node-negative disease; (c) EFS in patients with stage I disease; (d) OS in patients with stage I disease.
Fig. 3
Fig. 3
Impact of the IGG signature beyond tumor stage. Visual depiction showcasing the distinct contributions of variables to improve the overall fit of the prognostic model for both event-free survival (EFS) and overall survival (OS) outcomes. The sequence of variable inclusion in each model followed the order of tumor stage, nodal stage, and IGG signature. The assessment employed the likelihood-ratio chi-squared statistic as a measure of how well the model fits the data.
Fig. 4
Fig. 4
Kaplan–Meier estimates in TNBC according to the expression of the IGG-Clin risk score (quartiles). (a) EFS in the pooled dataset; (b) OS in the pooled dataset.
Fig. 5
Fig. 5
Association of the IGG signature with pCR in CALGB-40603 and BrighTNess datasets. (a, b) pCR rates according to the expression of the IGG signature according to quartiles in CALGB-40603 (a) and BrighTNess (b); (c, d) effect of carboplatin on pCR rates according to the expression of the IGG signature in (c) CALGB-40603 and (d) BrighTNess.
Fig. 6
Fig. 6
Kaplan–Meier estimates in TNBC according to the IGG-Clin score and the type of pathological response in the CALGB-40603 trial. EFS according to IGG-Clin score (quartiles) in patients with (a) residual disease or (b) pCR following neoadjuvant chemotherapy.
Fig. 7
Fig. 7
Immune infiltrate composition in TNBC based on IGG expression in the SCAN-B, BrighTNess and CALGB-40603 datasets. (a) Significant changes in immune cell types as determined by CIBERSORTx across IGG quartiles. Statistical differences were evaluated using a 2-way ANOVA considering both IGG quartiles and datasets, followed by Tukey's honest significant difference analysis; (b) Summary of the distribution of immune cell types as determined by CIBERSORTx across IGG quartiles. Percentages were calculated by averaging the expression of each cell type in each IGG quartile, with weighting based on the number of patients in each dataset; (c) Graphical representation of immune cells types associated with IGG in TNBC.
See this image and copyright information in PMC

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