Abstract PD04-08: Cell cycle algorithm correlates with grade of DCIS and p53 status, allows elimination of ‘intermediate grade’ disease and gives clinically meanignful information.

Abstract

Abstract We have previously shown that multi-parameter analysis of the DNA replication initiation machinery (Mcm2-7, geminin) and mitotic proteins (Plk1, Aurora A, H3S10ph), expressed during various phases of the cell division cycle, provides a method to accurately assess the proliferative state of dynamic tumour cell populations. We have shown that this novel form of cell cycle biomarker analysis allows separation of breast cancers into three discrete cell cycle phenotypes of major prognostic significance including (i) an out-of-cycle state, (ii) a G1-delayed/arrested state and (iii) an actively cycling state. Importantly, we identified groups of patients with apparently good grade cancers on routine clinicopathological criteria but who nevertheless exhibited the poor prognostic actively cycling phenotype (iii) and might therefore benefit from adjuvant chemotherapy. Additionally, we identified patients with typically poor prognosis tumours but which were actually cycling slowly (phenotype i or ii) and therefore likely not to have benefited from chemotherapy. Notably, when this cell cycle algorithm was used in a multi-variate analysis, the effect of Ki-67 disappeared. We have now applied the algorithm to 72 cases of DCIS (all of which were re-graded by one pathologist for consistency) and also to a TMA of 136 cases with known outcome from the UK DICS trial. There was excellent correlation between tumour grade and p53 status. The high grade DCIS was positively associated with a high cell cycle score (actively cycling phenotype iii; 28 out of 34 tumours) and low grade DCIS was associated with a low score (namely phenotypes i and ii; 13 out of 19). Interestingly, 7 of the 10 intermediate grade DCIS could be classified as phenotype, i or iii suggesting that the algorithm may be useful in stratifying this group of patients. A clinical correlation between phenotype III and recurrence and/or progression to invasive disease was evident. Further analysis of this from data derived from the TMAs generated from the UK DCIS trial will be presented. If the early findings are confirmed we may be able to solve the dilemma of which cases of DCIS need treatment and which we currently overtreat. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr PD04-08.