Immune Checkpoint Profiles in Luminal B Breast Cancer (Alliance)

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Abstract
Unlike estrogen receptor (ER)-negative breast cancer, ER-positive breast cancer outcome is less influenced by lymphocyte content, indicating the presence of immune tolerance mechanisms that may be specific to this disease subset. A supervised analysis of microarray data from the ACOSOG Z1031 (Alliance) neoadjuvant aromatase inhibitor (AI) trial identified upregulated genes in Luminal (Lum) B breast cancers that correlated with AI-resistant tumor proliferation (percentage of Ki67-positive cancer nuclei, Pearson r > 0.4) (33 cases Ki67 > 10% on AI) vs LumB breast cancers that were more AI sensitive (33 cases Ki67 < 10% on AI). Overrepresentation analysis was performed using WebGestalt. All statistical tests were two-sided. Thirty candidate genes positively correlated (r ≥ 0.4) with AI-resistant proliferation in LumB and were upregulated greater than twofold. Gene ontologies identified that the targetable immune checkpoint (IC) components IDO1, LAG3, and PD1 were overrepresented resistance candidates (P ≤ .001). High IDO1 mRNA was associated with poor prognosis in LumB disease (Molecular Taxonomy of Breast Cancer International Consortium, hazard ratio = 1.43, 95% confidence interval = 1.04 to 1.98, P = .03). IDO1 also statistically significantly correlated with STAT1 at protein level in LumB disease (Pearson r = 0.74). As a composite immune tolerance signature, expression of IFN-γ/STAT1 pathway components was associated with higher baseline Ki67, lower estrogen, and progesterone receptor mRNA levels and worse disease-specific survival (P = .002). In a tissue microarray analysis, IDO1 was observed in stromal cells and tumor-associated macrophages, with a higher incidence in LumB cases. Furthermore, IDO1 expression was associated with a macrophage mRNA signature (M1 by CIBERSORT Pearson r = 0.62 ) and by tissue microarray analysis. Targetable IC components are upregulated in the majority of endocrine therapy–resistant LumB cases. Our findings provide rationale for IC inhibition in poor-outcome ER-positive breast cancer.
Funding Information
  • Susan G. Komen Promise (PG12220321)
  • Cancer Prevention and Research Institute of Texas
  • CPRIT
  • Recruitment of Established Investigators (RR140033, U01CA214125)
  • MJE is a CPRIT scholar in cancer research
  • McNair Foundation scholar
  • Susan G. Komen Scholar (SAC170059, CCR18548157)
  • National Cancer Institute of the NIH (U10CA180821, U10CA180882, U24CA196171)
  • Alliance for Clinical Trials in Oncology (R01 CA095614, U10CA180833, U10CA180858)
  • AstraZeneca
  • Novartis Pharmaceutical Corporation
  • Pfizer, Inc.
  • NCI CPTAC grant (U24CA210954)
  • CPRIT (RR160027)
  • CPRIT Scholar in Cancer Research
  • McNair Scholar
  • NIH

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