Jeffrey Peppercorn

Background: Breast cancer (BC) in young patients is often identified at later stages, which can result in poor prognosis. It is important to investigate the factors influencing care delays and how delays affect outcomes. Methods: This study included women aged ≤40 years at diagnosis of stage 0–IV BC in the Young Women’s Breast Cancer Study enrolled between 2006 and 2016. Associations between patient and tumor factors and presentation delay (first symptom to provider visit, ≥90 days), diagnostic delay (presentation to diagnosis, ≥90 days), and treatment delay (diagnosis to treatment, ≥60 days) were estimated via logistic regression. Multivariable logistic models for delays were constructed via backward selection ( p ≤ .05 retained). Multivariable Cox proportional hazards models tested the association between delays and disease‐free survival (DFS) and overall survival (OS). Analyses were stratified by tumor subtype and stage. Results: Among 1071 women, there were 153 presentation, 120 diagnostic, and 228 treatment delays. In multivariable models, lower annual income was associated with higher odds of presentation delay, whereas pregnancy at diagnosis, family history of BC, and triple‐negative (TN) subtype were associated with lower odds. In HER2‐positive luminal B tumors, presentation delays were associated with later stage ( p < .001). Odds of diagnostic delay were higher for younger patients and lower for those with TN tumors. Patients with more aggressive tumor subtypes were less likely to have treatment delays. Delays were not associated with DFS or OS. Conclusions: In this cohort of young patients with BC, demographic and tumor factors were associated with delays in care. It is reassuring that delays did not influence disease outcomes.

Representative multiplex immunofluorescence image with nuclei (blue), CD8 (aqua), PDL1 (green), FOXP3 (yellow), PD1 (orange), CD3 (red), and cytokeratin (white) stains depicted.

Multiplex immunofluorescence staining conditions.

Representative multiplex immunofluorescence images with nuclei (blue), CD8 (aqua), FOXP3 (yellow), CD3 (red), and cytokeratin (white) stains depicted.

Tumor-infiltrating lymphocytes assessment workflow.

Multivariate survival analysis by moderate or marked versus absent or mild stromal lymphocytic infiltration, with adjustment for tumor grade, stage, and chemotherapy receipt.

Purpose:The role of tumor-infiltrating lymphocytes (TIL) remains unclear in hormone receptor (HR)–positive/HER2-negative breast cancer, particularly in young patients, whose immune microenvironment could be altered by age-related host and tumor differences.Experimental Design:Patients with stage I to III HR-positive/HER2-negative tumors were identified from a prospective cohort study of patients with breast cancer diagnosed at age ≤40 years. Multiplexed immunofluorescence and semiautomated quantitative software measured cytotoxic T, non–CD8 T, T regulatory, exhausted T, and PDL1+ cells in stroma and tumor. Univariate analyses assessed differences in clinicopathologic characteristics by high versus low immune infiltration, divided based on median. TIL subtypes were evaluated as a continuous variable per 10% increase in Cox regression analyses for invasive breast cancer–free survival, distant disease–free survival (DDFS), and overall survival, adjusted for clinicopathologic parameters.Results:Among 390 patients, high immune infiltration was associated with increasing age, Black race, grade 3 tumors, and metaplastic or micropapillary histologic subtypes. Over a median follow-up of 8 years, higher stromal and intratumoral non–CD8 T-cell infiltration, T regulatory–cell infiltration, and PDL1 expression were associated with improved invasive breast cancer–free survival. Higher intratumoral non–CD8 T-cell infiltration, T regulatory–cell infiltration, and PDL1 expression were associated with improved DDFS; higher stromal PDL1 expression was also associated with improved DDFS. Higher intratumoral cytotoxic T-cell infiltration and PDL1 expression were associated with improved overall survival.Conclusions:Characterization of immune subpopulations could help refine the prognostic value of TILs in young patients with HR-positive breast cancer, who may benefit from risk stratification for treatment individualization.See related commentary by Salgado and Kok, p. 2133

Pearson’s correlation coefficients between tumor-infiltrating lymphocyte subtypes within stroma, with p-values in parentheses.

Representativeness of Study Participants