Subtypes of high-grade breast ductal carcinoma in situ (DCIS): incidence and potential clinical impact

Abstract

Objective The purpose of this study was to investigate and classify the molecular subtypes of high-grade ductal carcinoma in situ (DCIS) and identify possible high-risk subtypes. The heterogenicity of DCIS with variable clinical and histopathological presentations has been recognized. Nevertheless, only histopathological grading and diameter are currently implemented in clinical decision-making following the diagnosis of DCIS. The molecular subtypes of DCIS and their IHC surrogate markers have not been defined in conventional treatment guidelines and recommendations. We applied the definitions of molecular subtypes according to the IHC surrogate markers defined for IBC and subclassified high-grade DCIS, accordingly. Methods Histopathological specimens were collected, revised, and regraded from 494 patients diagnosed with DCIS between 1996 and 2018. Other in situ and papillary lesions observed in breast biopsies were excluded from this study. 357 high-grade DCIS cases were submitted to IHC analysis. The markers investigated were ER, PR, HER2, and Ki67. Results 45 cases were classified as grade 1, 19 as grade 2, and 430 as grade 3. Sixty patients with high-grade DCIS had an additional invasive component in the surgical specimen. Thirty-three patients were diagnosed with recurrent DCIS or invasive cancer (minimum one year after their primary DCIS diagnosis). The proportions of luminal A and luminal B HER2-negative subtypes varied depending on whether 2011 or 2013 St. Gallen Consensus Conference guidelines were adopted. Luminal A was the most prevalent subtype, according to both classifications. The luminal B HER2-positive subtype was found in 22.1% of cases, HER2-enriched subtype in 21.8%, and TPN subtype in 5.6%. There were strong indications that HER2-enriched subtype was significantly more frequent among DCIS with invasive component (p = 0.0169). Conclusions High-grade DCIS exhibits all the molecular subtypes previously identified in IBC, but with a somewhat different distribution in our cohort. HER2-enriched subtype is substantially related to the presence of an invasive component in DCIS; consequently, it is regarded as a high-risk entity.

Low progesterone receptor levels in high-grade DCIS correlate with HER2 upregulation and the presence of invasive components

“…( 42 ) reported a significant difference between age and ER/PR expression, although they did not identify any significant variation between age and HER2 overexpression. In our earlier study, we identified that HER2 overexpression in cases classified as the HER2-enriched subtype was concurrent with early morphological invasive growth in high-grade DCIS ( 15 ). HER2 gene amplification in IBC is an independent poor prognostic factor ( 43 , 44 ).…”

“…Collected between 1996 and 2018, these samples represented 494 female patients diagnosed with DCIS of the breast. Experienced breast pathologists actively graded the histopathological specimens using the Van Nuys classification system ( 15 , 16 ). To our knowledge, this is the largest DCIS biobank that has been approved for cancer research purposes in Europe.…”

“…A total of 357 high-grade DCIS cases were submitted to IHC analysis, stained for ER, PR, HER2, and Ki67, and subjected to further studies. These were classified into their respective subtypes in accordance with the 2013 St. Gallen International Consensus Conference Guidelines, currently established for molecular subtyping of IBC lesions ( 15 ). Briefly, according to this classification ( 20 ), the LumA subtype was defined when ER was positive (≥ 1%) and/or PR was ≥ 20%, HER2 − , and Ki67 index was < 20%.…”

“…The general definitions of the molecular subtypes in IBC, according to IHC surrogate markers, are provided in Supplementary Table S1 ( 21 – 23 ). All procedures have been described in detail in our previous study ( 15 ). Each subtype was sorted into three subcategories: “Pure” ( n = 306) meaning those without an invasive component; “W/invasive” ( n = 51) meaning those with an invasive component; and “All” ( n = 357) meaning the entire group of the given subtype.…”

“…LumA and luminal B HER2-negative (LumB HER2 − ) cases together comprised 50.4%, luminal B HER2-positive (LumB HER2 + ) comprised 22.1%, HER2-enriched comprised 21.8%, and triple-negative (TPN) subtype comprised 5.6% of cases. We also identified the HER2-enriched subtype as a high-risk entity because it was significantly correlated with the presence of an invasive component ( 14 , 15 ). This study aimed to investigate the pivotal and well-established molecular breast cancer markers, ER, PR, and HER2, in the respective subtypes of human high-grade DCIS, aiming to identify those DCIS lesions that most probably will progress to IBC.…”