Quantitative analysis of breast cancer tissue composition and associations with tumor subtype

Linnea T. Olsson, Lindsay A. Williams, Bentley R. Midkiff, Erin L. Kirk, Melissa A. Troester, Benjamin C. Calhoun

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

The tumor microenvironment is an important determinant of breast cancer progression, but standard methods for describing the tumor microenvironment are lacking. Measures of microenvironment composition such as stromal area and immune infiltrate are labor-intensive and few large studies have systematically collected this data. However, digital histologic approaches are becoming more widely available, allowing high-throughput, quantitative estimation. We applied such methods to tissue microarrays of tumors from 1687 women (mean 4 cores per case) in the Carolina Breast Cancer Study Phase 3. Tumor composition was quantified as percentage of epithelium, stroma, adipose, and lymphocytic infiltrate (with the latter as presence/absence using a ≥1% cutoff). Composition proportions and presence/absence were evaluated in association with clinical and molecular features of breast cancer (intrinsic subtype and RNA-based risk of recurrence [ROR] scores) using multivariable linear and logistic regression. Lower stromal content was associated with aggressive tumor phenotypes, including triple-negative (31.1% vs. 41.6% in HR+/HER2-; RFD [95% CI]: −10.5%, [-13.1, −7.9]), Basal-like subtypes (29.0% vs. 44.0% in Luminal A; RFD [95% CI]: −14.9%, [-17.8, −12.0]), and high RNA-based PAM50 ROR scores (27.6% vs. 48.1% in ROR low; RFD [95% CI]: −20.5%, [24.3, 16.7]), after adjusting for age and race. HER2+ tumors also had lower stromal content, particularly among RNA-based HER2-enriched (35.2% vs. 44.0% in Luminal A; RFD [95% CI]: −8.8%, [-13.8, −3.8]). Similar associations were observed between immune infiltrate and tumor phenotypes. Quantitative digital image analysis of the breast cancer microenvironment showed significant associations with demographic characteristics and biological indicators of aggressive behavior.

Original languageEnglish (US)
Pages (from-to)84-92
Number of pages9
JournalHuman pathology
Volume123
DOIs
StatePublished - May 2022

Bibliographical note

Funding Information:
Funding/Support: This work was supported by P30 ES010126 , U01 CA179715 , P50 CA058223 , U01 ES19472 , R01 CA253450 , and the Susan G. Komen for the Cure, including a Komen Foundation Graduate Training in Disparities Research program grant.

Funding Information:
The Carolina Breast Cancer Study was supported by a grant from UNC Lineberger Comprehensive Cancer Center, which is funded by the University Cancer Research Fund of North Carolina, the Susan B Komen Foundation (OGUNC1202), the National Cancer Institute of the National Institutes of Health (P01CA151135), and the National Cancer Institute Specialized Program of Research Excellence (SPORE) in Breast Cancer (NIH/NCI P50-CA58223). This research recruited participants &/or obtained data with the assistance of Rapid Case Ascertainment, a collaboration between the North Carolina Central Cancer Registry and UNC Lineberger. RCA is supported by a grant from the National Cancer Institute of the National Institutes of Health (P30CA016086). The authors would like to acknowledge the University of North Carolina BioSpecimen Processing Facility for sample processing, storage, and sample disbursements ( http://bsp.web.unc.edu/ ). We are grateful to CBCS participants and study staff.

Publisher Copyright:
© 2022 The Authors

Keywords

  • Breast cancer
  • Digital histology
  • Microenvironment
  • Pathology
  • Stroma
  • Tumor-infiltrating lymphocytes (TILs)

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural

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