Integrated Molecular and Histologic Subtypes in Breast Cancer Risk and Survival

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  • March 21, 2019
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  • Williams, Lindsay
    • Affiliation: Gillings School of Global Public Health, Department of Epidemiology
Abstract
  • Background: Intrinsic breast cancer subtypes and histologic subtypes have distinct risk factor profiles. Ductal carcinoma, diagnosed in 60-80% of cases, shows intrinsic subtype diversity. Lobular and mixed ductal-lobular carcinomas, each diagnosed in up to 15% of cases, are predominantly Luminal A subtype. It is unclear whether reported risk factor and survival profiles by histologic subtype will persist in analyses restricted to Luminal A subtype. Methods: Using 4,359 invasive breast cancer cases from the Carolina Breast Cancer Study (1993-2013) we estimated tumor characteristic-histologic subtype associations and compared results to those in The Cancer Genome Atlas (TCGA). We estimated associations between reproductive risk factors and histologic subtypes. Finally, we evaluated associations between histologic subtype and survival. All association analyses were performed across all tumors regardless of molecular subtype and among tumors of Luminal A subtype (clinical and RNA-based) only. Results: Tumor and molecular characteristics of lobular and mixed carcinomas were quantitively different from ductal carcinomas, overall and among Luminal A subtype. Associations between histologic subtypes and tumor and genomic characteristics were similar in CBCS and TCGA. Lobular tumors were predominantly Luminal A subtype and had fewer TP53 pathway defects than ductal tumors. In the analysis of reproductive risk factors by histologic subtype, case-case analyses suggested significant differences between lobular and ductal tumors for older age (≥26 years) at first birth, lactation duration >12 months, and oral contraceptive use. These associations among all tumors did not vary by race and were similar in direction and magnitude among Luminal A tumors only. Compared to ductal tumors, lobular and mixed tumors were inversely associated with breast cancer-specific death from 0-10 years after diagnosis and positively associated with breast cancer-specific death at great than 10 years since diagnosis, even among Luminal A tumors only. Conclusions: We observed that histology was strongly associated with molecular tumor characteristics in the CBCS and TCGA, showing that the vast majority of lobular tumors are Luminal A subtype. Risk factor profiles and breast cancer-specific survival associations with histologic subtype among Luminal A tumors were similar in direction and magnitude to those observed among all tumors regardless of molecular subtype.
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  • In Copyright
Advisor
  • Nichols, Hazel
  • Olshan, Andrew
  • Love, Michael
  • Hoadley, Katherine
  • Troester, Melissa
Degree
  • Doctor of Philosophy
Degree granting institution
  • University of North Carolina at Chapel Hill
Graduation year
  • 2017
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