Collagen Organization in Relation to Ductal Carcinoma In Situ Pathology and Outcomes

Brian L Sprague^{1

2

3}, Pamela M Vacek^{2

4}, Sophie E Mulrow⁵, Mark F Evans^{2

6}, Amy Trentham-Dietz^{7

8}, Sally D Herschorn^{2

3}, Ted A James⁹, Nuntida Surachaicharn¹⁰, Adib Keikhosravi¹¹, Kevin W Eliceiri^{8

11}, Donald L Weaver^#^{2

6}, Matthew W Conklin^#^{12

10}

Affiliations

¹ Department of Surgery, Office of Health Promotion Research, University of Vermont Larner College of Medicine, Burlington, Vermont. Brian.Sprague@uvm.edu mwconklin@wisc.edu.
² University of Vermont Cancer Center, University of Vermont Larner College of Medicine, Burlington, Vermont.
³ Department of Radiology, University of Vermont Larner College of Medicine, Burlington, Vermont.
⁴ Department of Medical Biostatistics, University of Vermont, Burlington, Vermont.
⁵ Department of Surgery, Office of Health Promotion Research, University of Vermont Larner College of Medicine, Burlington, Vermont.
⁶ Department of Pathology and Laboratory Medicine, University of Vermont Larner College of Medicine, Burlington, Vermont.
⁷ Department of Population Health Sciences, University of Wisconsin-Madison, Madison, Wisconsin.
⁸ Carbone Cancer Center, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin.
⁹ Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
¹⁰ Department of Cell and Regenerative Biology, University of Wisconsin-Madison, Madison, Wisconsin.
¹¹ Department of Biomedical Engineering, Laboratory for Optical and Computations Instrumentation, University of Wisconsin-Madison, Madison, Wisconsin.
¹² Carbone Cancer Center, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin. Brian.Sprague@uvm.edu mwconklin@wisc.edu.

^# Contributed equally.

PMID: 33082201
PMCID: PMC7855820
DOI: 10.1158/1055-9965.EPI-20-0889

Collagen Organization in Relation to Ductal Carcinoma In Situ Pathology and Outcomes

Brian L Sprague et al. Cancer Epidemiol Biomarkers Prev. 2021 Jan.

. 2021 Jan;30(1):80-88.

doi: 10.1158/1055-9965.EPI-20-0889. Epub 2020 Oct 20.

Authors

Affiliations

¹ Department of Surgery, Office of Health Promotion Research, University of Vermont Larner College of Medicine, Burlington, Vermont. Brian.Sprague@uvm.edu mwconklin@wisc.edu.
² University of Vermont Cancer Center, University of Vermont Larner College of Medicine, Burlington, Vermont.
³ Department of Radiology, University of Vermont Larner College of Medicine, Burlington, Vermont.
⁴ Department of Medical Biostatistics, University of Vermont, Burlington, Vermont.
⁵ Department of Surgery, Office of Health Promotion Research, University of Vermont Larner College of Medicine, Burlington, Vermont.
⁶ Department of Pathology and Laboratory Medicine, University of Vermont Larner College of Medicine, Burlington, Vermont.
⁷ Department of Population Health Sciences, University of Wisconsin-Madison, Madison, Wisconsin.
⁸ Carbone Cancer Center, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin.
⁹ Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
¹⁰ Department of Cell and Regenerative Biology, University of Wisconsin-Madison, Madison, Wisconsin.
¹¹ Department of Biomedical Engineering, Laboratory for Optical and Computations Instrumentation, University of Wisconsin-Madison, Madison, Wisconsin.
¹² Carbone Cancer Center, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin. Brian.Sprague@uvm.edu mwconklin@wisc.edu.

^# Contributed equally.

PMID: 33082201
PMCID: PMC7855820
DOI: 10.1158/1055-9965.EPI-20-0889

Abstract

Background: There is widespread interest in discriminating indolent from aggressive ductal carcinoma in situ (DCIS). We sought to evaluate collagen organization in the DCIS tumor microenvironment in relation to pathologic characteristics and patient outcomes.

Methods: We retrieved fixed tissue specimens for 90 DCIS cases within the population-based Vermont DCIS Cohort. We imaged collagen fibers within 75 μm of the tumor/stromal boundary on hematoxylin and eosin-stained slides using multiphoton microscopy with second-harmonic generation. Automated software quantified collagen fiber length, width, straightness, density, alignment, and angle to the tumor/stroma boundary. Factor analysis identified linear combinations of collagen fiber features representing composite attributes of collagen organization.

Results: Multiple collagen features were associated with DCIS grade, necrosis pattern, or periductal fibrosis (P < 0.05). After adjusting for treatments and nuclear grade, risk of recurrence (defined as any second breast cancer diagnosis) was lower among cases with greater collagen fiber width [hazard ratio (HR), 0.57 per one standard deviation increase; 95% confidence interval (CI), 0.39-0.84] and fiber density (HR, 0.60; 95% CI, 0.42-0.85), whereas risk was elevated among DCIS cases with higher fiber straightness (HR, 1.47; 95% CI, 1.05-2.06) and distance to the nearest two fibers (HR, 1.47; 95% CI, 1.06-2.02). Fiber length, alignment, and fiber angle were not associated with recurrence (P > 0.05). Five composite factors were identified, accounting for 72.4% of the total variability among fibers; three were inversely associated with recurrence (HRs ranging from 0.60 to 0.67; P ≤ 0.01).

Conclusions: Multiple aspects of collagen organization around DCIS lesions are associated with recurrence risk.

Impact: Collagen organization should be considered in the development of prognostic DCIS biomarker signatures.

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Figures

**Figure 1.**
Sample multiphoton microscopy images of collagen fibers, illustrating cases with different collagen features. Panel A shows an area of DCIS surrounded by short, curvy, dense fibers. Panel B shows an area of DCIS surrounded with long, straight, high alignment fibers. Scale bar, 100 μm.

See this image and copyright information in PMC

References

1. Conklin MW, Gangnon RE, Sprague BL, Van Gemert L, Hampton JM, Eliceiri KW, et al. Collagen Alignment as a Predictor of Recurrence after Ductal Carcinoma In Situ. Cancer Epidemiol Biomarkers Prev 2018;27(2):138–145. - PMC - PubMed
1. Miglioretti DL, Zhu W, Kerlikowske K, Sprague BL, Onega T, Buist DS, et al. Breast Tumor Prognostic Characteristics and Biennial vs Annual Mammography, Age, and Menopausal Status. JAMA Oncol 2015;1(8):1069–77. - PMC - PubMed
1. Sprague BL, McLaughlin V, Hampton JM, Newcomb PA, Trentham-Dietz A. Disease-free survival by treatment after a DCIS diagnosis in a population-based cohort study. Breast cancer research and treatment 2013;141(1):145–154. - PMC - PubMed
1. Duffy SW, Agbaje O, Tabar L, Vitak B, Bjurstam N, Bjorneld L, et al. Overdiagnosis and overtreatment of breast cancer: estimates of overdiagnosis from two trials of mammographic screening for breast cancer. Breast Cancer Res 2005;7(6):258–65. - PMC - PubMed
1. Ernster VL, Barclay J. Increases in ductal carcinoma in situ (DCIS) of the breast in relation to mammography: a dilemma. J Natl Cancer Inst Monogr 1997, (22):151–6. - PubMed

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Collagen Organization in Relation to Ductal Carcinoma In Situ Pathology and Outcomes

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Collagen Organization in Relation to Ductal Carcinoma In Situ Pathology and Outcomes

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