Bratislava Medical Journal Vol.115, No.7, p.445-451, 2014

 Background: Recent studies have showed a significant association between the combination of COX-2, p16 and Ki67 overexpression and incidence of subsequent invasive carcinoma in a subgroup of treated ductal carcinoma in situ (DCIS) and the indicated prognostic value of COX-2, p16 and Ki67 in early breast cancer. Based on the continual model of carcinogenesis and the mentioned results, we hypothesize, that if COX-2, p16 and Ki67 expression is prognostic for DCIS future behaviour, the expression level of the markers correlates also with different stages of breast carcinomas such as DCIS, microinvasive cancer and early invasive cancer with an extensive intraductal compound.
The aim of this study was to compare the expression of COX-2, p16 and Ki67 in different stages of breast carcinoma such as pure DCIS, microinvasive cancer (T1mic) and invasive ductal carcinoma with an extensive intraductal component (IDC with EIC). The expression was assessed only in in situ component of the three subgroups (DCIS, T1mic, EIC) in order to show a possible correlation of COX-2, p16 and Ki67 with different stages of carcinogenesis.
Methods: We carried out a retrospective study using immunohistochemical staining to evaluate the expression of the markers COX-2, p16 and Ki67 in in situ lesions within three subgroups of tumors with the rising extant of invasive compound: in pure DCIS, microinvasive carcinoma (T1mic) and invasive carcinoma with extensive in situ component (IDC with EIC). Additionally, we performed a correlation analysis between the tumor subgroups and patients history data (age, parity, age of menarche, family and personal cancer history, breast feeding lengths, contraception intake, chest irradiation) as well as some of the tumor characteristics (tumor grade, multicentricity, necrosis).
Results: Distribution of p16 expression differed significantly among the three diagnoses.

P16 score 1 was highest in the DCIS group whereas the lowest proportion was in IDC and p16 overexpression (score 2, 3) maintained this tendency (overexpression proportion in DCIS < T1mic < IDC), though this was not significant.

The frequency of COX-2 and p16 overexpression (phenotype COX-2+p16+) was higher in EIC within invasive carcinoma in comparison to DCIS and T1mic and was rising gradually with the severity of the diagnosis (proportion in DCIS < T1mic < IDC).

Conclusion: This is the first published study ever assessing the expression of COX-2, p16 and Ki67 markers in different breast tumors containing DCIS compound. Our results showed an increasing expression pattern of COX-2 and p16 with the rising severity of the diagnosis (expression was measured exclusively in in situ lesions within tumors containing different extant of invasiveness). The same relationship was showed for p16 marker alone. These data support different expression pattern of COX-2 and p16 markers in combination and p16 marker alone in “in situ lesions” according to the stage of carcinogenesis. This fact might be useful in the evaluation of further behaviour of early breast tumors (Tab. 3, Fig. 8, Ref. 29).