268P - Impact of B cell and plasma cell infiltration on survival in early-stage breast cancer (BC) without recurrence

Background

Previous research in early-stage BC has established the association of a 14-gene immunoglobulin/B-cell (IGG) signature (sig) with a reduced risk of distant metastasis. However, the relationship between this signature and patient longevity, in the absence of a BC recurrence, is unknown.

Methods

We employed competing risk analyses to test the association between the IGG sig, age, and longevity, where the competing event was prior relapse. Longevity was defined as survival or death without a documented BC relapse. The analysis was performed in 3 BC cohorts: METABRIC (n=1,133), SCAN-B (n=4,470), and TCGA (n=936). We conducted spatial proteomics on 39 immune-related proteins within the tumor stroma and assessed the presence of tertiary lymphoid structures (TLS) in 132 FFPE BC tumors with varying IGG levels. We performed single-cell RNA sequencing (scRNAseq) of CD45-positive cells from 6 fresh BC samples, and characterized B-cell and T-cell receptors (BCR and TCR) across different IGG levels using the immunoSEQ assay in 33 FFPE BC tumors and analyzing bulk RNAseq data of the CALGB-40601 BC trial (n=264).

Results

The IGG sig was significantly linked to increased longevity across all cohorts (p<0.001). A moderate inverse correlation was found between the IGG sig and age. Notably, in patients aged 40-70 years, the IGG sig was significantly associated with longevity independently of age (p<0.001). IGG-high tumors showed enrichment in TLS+ and higher expression of plasma cell and memory B cell marker (CD27), activated T cells (ICOS), antigen-presenting cells (CD40), and lower levels of stromal fibronectin. ImmunoSEQ, bulk and scRNAseq analyses showed that IGG high tumors had a tendency towards higher B cell infiltration and demonstrated a TCR and BCR polyclonal repertoire, compared to IGG low tumors (Simpson, Shannon p<0.001).

Conclusions

The IGG sig serves as a prognostic biomarker for both recurrence and extended longevity of patients with early-stage BC. Its association with longevity might rely on the detection of enhanced immune fitness, which could better protect against infections and other cancers. Our results open potential new avenues for develop tailored therapy strategies, enhancing patient outcomes and quality of life.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Instituto de Salud Carlos III and Breast cancer research foundation.

Disclosure

L. Pare Brunet: Financial Interests, Institutional, Full or part-time Employment: Reveal Genomics S.L.; Financial Interests, Institutional, Other, Patent pending: In vitro method for the prognosis of patients suffering from HER2-positive breast cancer - 905333: SOLTI; Financial Interests, Institutional, Other, Patent filed: EP23382703: Reveal Genomics S.L.; Financial Interests, Institutional, Other, Patent filed: EP23383369: Reveal Genomics S.L. E. Segui Solis: Financial Interests, Personal, Invited Speaker: Novartis, Veracyte, Pfizer, Daiichi Sankyo, Eisai; Financial Interests, Personal, Advisory Board: Pfizer, Seagen; Financial Interests, Personal, Full or part-time Employment: SOLTI; Financial Interests, Personal, Research Grant: Amgen. G. Villacampa: Financial Interests, Personal, Invited Speaker, Invited speaker in a course: MSD; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Invited Speaker, Invited speaker in an internal training: Pierre Fabrer, GSK; Financial Interests, Personal, Invited Speaker, Internal discussion about the interpretation of some published results: Pfizer; Financial Interests, Personal, Other, Collaborations with specific projects: Reveal Genomics. W. Buckingham: Financial Interests, Institutional, Full or part-time Employment, Employed by Reveal Genomics SL: Reveal Genomics SL; Financial Interests, Personal, Stocks/Shares, Spouse stock ownership: Natera Inc. A. Vivancos: Financial Interests, Personal, Advisory Board: Roche, Bristol Myers Squibb, Guardant Health, Bayer, Incyte; Financial Interests, Personal, Stocks/Shares: Reveal Genomics; Financial Interests, Institutional, Research Grant, Preclinical Research Grant: Bristol Myers Squibb, Roche, Incyte. P. Villagrasa Gonzalez: Financial Interests, Personal, Full or part-time Employment, CEO and co-founder of the company: Reveal Genomics S.L.; Financial Interests, Personal, Ownership Interest: Reveal Genomics S.L.; Financial Interests, Personal, Royalties, PCT/EP2021/086493 - In Vitro Method For The Prognosis Of Patients Suffering From HER2-Positive Breast Cancer: Reveal Genomics S.L. C.M. Perou: Financial Interests, Personal, Other, consultant: GeneCentric Therapeutics, Bioclassifier LLC, Reveal Genomics; Financial Interests, Personal, Member of Board of Directors: GeneCentric Therapeutics; Financial Interests, Personal, Ownership Interest: GeneCentric Therapeutics, Bioclassifier LLC, Reveal Genomics; Financial Interests, Personal, Royalties: Bioclassifier LLC. A. Prat: Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Personal, Invited Speaker, Lecture fees: Novartis, Daiichi Sankyo; Financial Interests, Personal, Advisory Board, Advisory role/consultancy: Novartis, Pfizer, Peptomyc; Financial Interests, Institutional, Invited Speaker, Clinical trials: Daiichi Sankyo; Financial Interests, Institutional, Other, Contracted research: Boehringer, Medica Scientia inno. Research; Financial Interests, Personal, Advisory Board: AstraZeneca, Reveal Genomics, 1TRIALSP, S.L.; Financial Interests, Personal, Member of Board of Directors, Leadership role: Reveal Genomics, SL.; Financial Interests, Personal, Stocks/Shares: Reveal Genomics; Financial Interests, Personal, Royalties: Reveal Genomics, International Oncology Bureau, S.L.,; Financial Interests, Institutional, Local PI: Roche, AstraZeneca; Financial Interests, Personal and Institutional, Steering Committee Member: Daiichi Sankyo; Financial Interests, Institutional, Coordinating PI: Novartis; Financial Interests, Institutional, Funding: Reveal Genomics; Non-Financial Interests, Institutional, Other, Leadership roles: Patronage committee: Actitud Frente al Cáncer Foundation; Non-Financial Interests, Personal, Other, Asociación Española de Investigación sobre el Cáncer: ASEICA; Non-Financial Interests, Personal, Other, Research Foundation that gives grants to researchers: FERO. F. Braso Maristany: Non-Financial Interests, Personal and Institutional, Other, Consulting fees: Reveal Genomics. All other authors have declared no conflicts of interest.