Integrating Tumor-Intrinsic and Immunologic Factors to Identify Immunogenic Breast Cancers from a Low-Risk Cohort: Results from the Randomized SweBCG91RT Trial

Abstract

Purpose: The local immune infiltrate's influence on tumor progression may be closely linked to tumor-intrinsic factors. The study aimed to investigate whether integrating immunologic and tumor-intrinsic factors can identify patients from a low-risk cohort who may be candidates for radiotherapy (RT) de-escalation.

Experimental design: The SweBCG91RT trial included 1,178 patients with stage I to IIA breast cancer, randomized to breast-conserving surgery with or without adjuvant RT, and followed for a median of 15.2 years. We trained two models designed to capture immunologic activity and immunomodulatory tumor-intrinsic qualities, respectively. We then analyzed if combining these two variables could further stratify tumors, allowing for identifying a subgroup where RT de-escalation is feasible, despite clinical indicators of a high risk of ipsilateral breast tumor recurrence (IBTR).

Results: The prognostic effect of the immunologic model could be predicted by the tumor-intrinsic model (Pinteraction = 0.01). By integrating measurements of the immunologic- and tumor-intrinsic models, patients who benefited from an active immune infiltrate could be identified. These patients benefited from standard RT (HR, 0.28; 95% CI, 0.09-0.85; P = 0.025) and had a 5.4% 10-year incidence of IBTR after irradiation despite high-risk genomic indicators and a low frequency of systemic therapy. In contrast, high-risk tumors without an immune infiltrate had a high 10-year incidence of IBTR despite RT treatment (19.5%; 95% CI, 12.2-30.3).

Conclusions: Integrating tumor-intrinsic and immunologic factors may identify immunogenic tumors in early-stage breast cancer populations dominated by ER-positive tumors. Patients who benefit from an activated immune infiltrate may be candidates for RT de-escalation.

Figure 1.

CONSORT diagram of the SweBCG91RT cohort. In unadjusted analyses, all patients with available gene expression and clinical information were included (n = 764). In multivariable analysis, patients with information of all included covariates were included (n = 739).

Figure 2.

Cumulative incidence of IBTR in the SweBCG91RT cohort within different percentiles of Immunescore and Proliferative Index, and depending on radiotherapy (RT). The risk of IBTR and benefit from RT were investigated along the axes of Immunescore and Proliferative Index. Among tumors with high values of Proliferative Index, increased Immunescore values were associated with a favorable prognostic effect and increased benefit from RT. This was not seen among tumors with low Proliferative Index values. The worst prognosis and least benefit from RT was seen among tumors with a high Proliferative Index but low Immunescore.

Figure 3.

A–C, Cumulative incidence of IBTR among patients from the SweBCG91RT cohort aged <70 with grade III tumors or aged <60 with tumors of any histologic grade depending on RT and on a model integrating immunological and tumor-intrinsic qualities. High-risk patients (<60 years of age or <70 years with histologic grade III) were stratified into tertiles based on a model that integrates Immunescore and Proliferative Index to predict the prognostic effect of an immune infiltrate based on tumor-intrinsic characteristics. The prognosis and benefit from RT were analyzed to understand if combining immunologic biomarkers and tumor-intrinsic characteristics may improve RT individualization.