Gene Expression Signatures of BRCAness and Tumor Inflammation Define Subgroups of Early-Stage Hormone Receptor–Positive Breast Cancer Patients

Abstract

Purpose: Patients with estrogen receptor– and/or progesterone receptor–positive, early breast cancer benefit from hormonal treatment, yet high global death burdens due to high prevalence and long-term recurrence risk call for biomarkers to guide additional treatment approaches. Experimental Design: From a prospective, observational study of postmenopausal early breast cancer patients treated with tamoxifen or aromatase inhibitors, gene expression analyses of 612 tumors was performed using the NanoString Breast Cancer 360 panel to interrogate 23 breast cancer pathways. Candidate signatures associated with disease subtype and event-free survival (EFS) were obtained by cluster analysis, Cox modeling, and conditional inference trees, and were independently tested in 613 patients from BreastMark. Tumor-infiltrating lymphocytes (TIL) were assessed on tissue sections, and mutational burden was assessed in 36 tumors by whole-exome sequencing. Results: PAM50-derived classification distinguished lower-risk (Luminal A) from higher-risk subtypes (Luminal B, P = 0.04; HER2, P = 0.006; Basal, P = 0.008). In higher-risk patients, shorter EFS was associated with low androgen receptor [HR = 3.61; 95% confidence interval (CI), 1.72–7.56; P = 0.001] or high BRCAness signature expression (HR = 3.58; 95% CI, 1.19–10.7; P = 0.023). BRCAness was independently confirmed as a predictor of shorter EFS (HR = 2.64; 95% CI, 1.31–5.34; P = 0.007). About 13%–15% of patients, enriched for high-grade, higher-risk subtypes (P ≤ 0.0001), had strong expression of the Tumor Inflammation Signature (TIS) suggestive of an inhibited antitumor immune response. TIS scores were strongly associated with TIL numbers (P < 1e-30) but not with tumor mutation status. Conclusions: BRCA-related DNA repair deficiency and suppressed tumor immune responses may be clinically relevant predictors of endocrine therapy complementing treatment options in subgroups of hormone-sensitive early breast cancer.

Estrogen receptor‐low breast cancer: Biology chaos and treatment paradox

“…Given that accumulating data support that the immune system plays a crucial role in breast cancer, and gene expression signatures of tumor inflammation define subgroups of early ER‐positive breast cancer [ 77 ], immunotherapy deserves to be explored in subgroups of ER‐positive patients. There is evidence that PD‐1/PD‐L1 signaling antagonists may have meaningful clinical activity in some patients with ER‐positive breast cancers [ 78 ].…”

Best Practices for Spatial Profiling for Breast Cancer Research with the GeoMx® Digital Spatial Profiler

“…Breast cancer is a heterogenous disease, both biologically and clinically, with a high degree of inter-and intra-patient variability that is intrinsic to the tumor cells and in the cellular and molecular composition of the tumor microenvironment (TME) [3][4][5][6][7][8]. Clinically, the diversity manifests in patients with respect to response to therapy and prognosis [3,[9][10][11][12][13].…”

Analysis of Genomic Alterations Associated with Recurrence in Early Stage HER2-Positive Breast Cancer

“…Liang et al reported that elevated levels of CXCL9 mRNA were associated with favorable outcomes in HR-negative breast cancer and CXCL9 was correlated with immune cell infiltration and immune-related biomarkers [ 43 ]. TIS score was developed as a predictive biomarker of ICIs from a large cohort of pembrolizumab-treated patients across nine different tumor types and the predictive utility of TIS score has been verified in many other studies [ 15 , 44 , 45 , 46 ]. Schroth et al reported that two gene signatures including BRCAness and TIS score, were associated with clinical outcome or presence of tumor immunogenicity in HR-positive early breast cancer [ 46 ].…”

“…TIS score was developed as a predictive biomarker of ICIs from a large cohort of pembrolizumab-treated patients across nine different tumor types and the predictive utility of TIS score has been verified in many other studies [ 15 , 44 , 45 , 46 ]. Schroth et al reported that two gene signatures including BRCAness and TIS score, were associated with clinical outcome or presence of tumor immunogenicity in HR-positive early breast cancer [ 46 ]. TIS scores were strongly associated with stromal TIL infiltrates, but TIS and TIL features showed only partial overlap [ 46 ].…”