Genomic landscape of ductal carcinoma in situ and association with progression

Abstract

Purpose: The detection rate of breast ductal carcinoma in situ (DCIS) has increased significantly, raising the concern that DCIS is overdiagnosed and overtreated. Therefore, there is an unmet clinical need to better predict the risk of progression among DCIS patients. Our hypothesis is that by combining molecular signatures with clinicopathologic features, we can elucidate the biology of breast cancer progression, and risk-stratify patients with DCIS.

Methods: Targeted exon sequencing with a custom panel of 223 genes/regions was performed for 125 DCIS cases. Among them, 60 were from cases having concurrent or subsequent invasive breast cancer (IBC) (DCIS + IBC group), and 65 from cases with no IBC development over a median follow-up of 13 years (DCIS-only group). Copy number alterations in chromosome 1q32, 8q24, and 11q13 were analyzed using fluorescence in situ hybridization (FISH). Multivariable logistic regression models were fit to the outcome of DCIS progression to IBC as functions of demographic and clinical features.

Results: We observed recurrent variants of known IBC-related mutations, and the most commonly mutated genes in DCIS were PIK3CA (34.4%) and TP53 (18.4%). There was an inverse association between PIK3CA kinase domain mutations and progression (Odds Ratio [OR] 10.2, p < 0.05). Copy number variations in 1q32 and 8q24 were associated with progression (OR 9.3 and 46, respectively; both p < 0.05).

Conclusions: PIK3CA kinase domain mutations and the absence of copy number gains in DCIS are protective against progression to IBC. These results may guide efforts to distinguish low-risk from high-risk DCIS.

Keywords: Breast cancer; Copy number variant; Ductal carcinoma in situ; PIK3CA.

Figure 1:

Genomic landscape of DCIS. (A) Distributions of known recurrent IBC-associated variants are (A) displayed in a bar graph with the number of cases denoted above the bars; (B) displayed in a heat map. In the group of DCIS+IBC, cases with subsequent IBC events are highlighted in the boxes.

Figure 2:

Distribution of PIK3CA mutations in two groups of DCIS cases. The number in the circles depicts the number of DCIS cases harboring the mutation in that particular position. To note, one of the DCIS-only cases exhibited two PIK3CA-KD variants.