Abstract
Human invasive breast cancers (IBC) show enormous histologic and biological diversity. This study comprehensively evaluated diversity in ductal carcinoma in situ (DCIS), the immediate precursors of IBCs. The extent of diversity for conventional histologic grade and standard prognostic biomarkers assessed by immunohistochemistry was evaluated in a series of pure DCIS (n = 200) compared with a contemporaneous series of IBCs (n = 200). A subset of the DCIS (n = 25) was evaluated by DNA microarrays for the presence of luminal, basal, and erbB2 intrinsic subtypes. The extent of diversity within individual cases of DCIS (n = 120) was determined by assessing multiple regions independently for histologic (nuclear) grade and several biomarkers by immunohistochemistry, which approximate microarrays in determining intrinsic subtypes. DCIS showed a broad distribution of conventional histologic grades and standard biomarkers ranging from well to poorly differentiated, nearly identical to IBCs. Microarrays showed the same intrinsic subtypes in DCIS as in IBCs. However, higher resolution analysis showed that multiple histologic grades, biomarker phenotypes, and intrinsic subtypes often coexist within the same DCIS, and these diverse regions probably compete for dominance. Diversity within cases of DCIS was highly correlated with mutated p53 (P = 0.0007). These results support the hypothesis that poorly differentiated DCIS gradually evolve from well-differentiated DCIS by randomly acquiring genetic defects resulting in increasingly abnormal cellular features. This diversity is amplified by defects resulting in genetic instability (e.g., p53 mutation), and the alterations are propagated to IBC in a manner independent of progression to invasion.
Highlights
Human invasive breast cancers (IBC) show enormous histologic and biological diversity
These issues are important clinically because biological diversity in ductal carcinoma in situ (DCIS) may influence the rate of progression to IBC, diversity propagated from DCIS to IBC may influence prognosis and sensitivity to specific therapies, and breast cancer prevention strategies should be based on an accurate understanding of how breast cancers evolve to be truly effective
The distribution of histologic score (H-score) and biomarkers were nearly identical in the IBCs and their DCIS component
Summary
Human invasive breast cancers (IBC) show enormous histologic and biological diversity. ADH is widely regarded as the nonobligate precursor of noncomedo/low-grade DCIS, because they show similar well-differentiated features, but not of comedo/high-grade DCIS, because of their dissimilar poorly differentiated features, leading to speculation that the latter pursue a different course of evolution from occult precursors and the evolution of intermediate-grade lesions are essentially ignored These issues are important clinically because biological diversity in DCIS may influence the rate of progression to IBC, diversity propagated from DCIS to IBC may influence prognosis and sensitivity to specific therapies, and breast cancer prevention strategies should be based on an accurate understanding of how breast cancers evolve to be truly effective. The purpose of this study was to comprehensively characterize the histologic and biological diversity of DCIS compared with IBC to help further our understanding of DCIS and its role in breast cancer evolution
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