Table 1.
Clinical sample information of the invasive cancer components classified by ER status in patients with IDC and DCIS (n = 36).
Figure 1.
Evaluation of intra-individual DCIS heterogeneity among patients (n = 36) concurrently diagnosed with IDC and DCIS.
(A) Examples of intra-individual homogeneity and heterogeneity in IHC marker expression of DCIS lesions. In an example of a homogeneous case (left), expression of all markers is similar across DCIS lesions. All markers within this case were classified as having no variable expression; therefore, this case is not considered to have intra-individual heterogeneity in the DCIS lesions. The example of a heterogeneous case on the right panels has variable expression of ER, PR, Ki-67, and p53 (highlighted in red; not all lesions shown in figure). Because more than three markers exhibited variable expression, this case has a high-degree of heterogeneity within the DCIS lesions. All but the top panels were taken at 100× magnification. (B) Percentage of cases exhibiting variable expression of IHC markers. For each IHC marker (i.e., p53, ER, PR, Ki-67, HER2, or p16) in an individual case to be considered as having variable expression, at least 20% of the DCIS lesions were required to have different expression levels compared to the majority of lesions. P-values represent how significant the differences are relative to a hypothesized baseline value of 10% variability in staining. (C) Intra-individual heterogeneity in DCIS. Cases were considered as having a moderate- or high-degree of heterogeneity if at least 2/6 or 3/6 markers, respectively were classified as having variable marker expression.
Figure 2.
IHC marker scores and DCIS classification among individual DCIS lesions from patients with IDC and DCIS (n = 36).
(A) Heat map of IHC markers for DCIS lesions. This heat map illustrates marker scoring for each individual DCIS lesion across six IHC markers. The individual lesions are aligned in columns and the unique patients are aligned in rows. (B) Molecular subtypes of DCIS lesions, adjacent TDLU, and IDC for each case. Subtypes including luminal A-like (ER+ and/or PR+, HER2−), luminal B-like (ER+ and/or PR+, HER2+), HER2+-like (ER−, PR−, HER2+), and basal-like/triple negative (ER−, PR−, HER2−) are classified according to hormone receptor status. (Lum: luminal; BL: basal-like; TDLU: terminal duct lobular units; blank: data is not available) (C). By comparing DCIS lesions with the molecular subtypes of adjacent IDC and the hormone receptor status in adjacent TDLU, DCIS lesions from each IDC-DCIS case were first classified into two subgroups based on the molecular subtypes of adjacent IDC: DCIS Subgroup I, which presented different molecular subtypes from the adjacent IDC; DCIS Subgroup II, which presented the same molecular subtypes as adjacent IDC. Then the Subgroup II DCIS lesions were further divided into Subgroup IIa (with the same molecular subtypes as both adjacent IDC and TDLU) and Subgroup IIb (with the same molecular subtypes as the adjacent IDC but not the same subtypes as the adjacent TDLU).
Table 2.
Associations between clinical characteristics and intra-individual DCIS heterogeneity in patients with IDC and DCIS (n = 36).
Table 3.
Association between IHC marker scores and molecular subtypes among individual DCIS lesions from patients with IDC and DCIS (n = 36).
Table 4.
Association between IHC marker scores and individual DCIS lesions classified based on molecular subtypes of adjacent IDC and TDLU from patients with IDC and DCIS (n = 36).
Figure 3.
Identification of a “highly-aggressive” DCIS subgroup.
DCIS lesions are sub-classified according to the molecular subtypes of adjacent TDLU and IDC (Model 1: TDLU and IDC have the same molecular subtypes; Model 2: TDLU and IDC have different molecular subtypes). By comparing Ki-67, p53 and p16 IHC scores, DCIS Subgroup IIb, which had the same molecular subtypes as the adjacent IDC but not the same subtypes as the adjacent TDLU, represents a “highly-aggressive” or “high-risk” subpopulation of DCIS which are putatively direct precursor of adjacent IDC, while DCIS Subgroups I and likely IIa represent “less-aggressive” or “low-risk” subpopulations which either require additional (epi)genetic changes or are not able to directly progress into IDC.