Cellular accumulation of p53 protein: an independent prognostic factor in stage II breast cancer.

The p53 gene product is a tumour suppressor protein, and alterations of the protein are common in human cancer. Previous studies have focused on nuclear accumulation of p53. To investigate if cytoplasmic accumulation of p53 strengthens the relationships to different pathobiological variables and distant recurrence-free survival in breast cancer, tumours from 164 stage II patients were examined with the monoclonal antibody PAb1801. Nine per cent of the tumours were nuclear positive and 21% were cytoplasmic positive. Cellular p53 accumulation, related to the nucleus or the cytoplasm or both, showed stronger associations with pathobiological variables than nuclear accumulation alone. Accumulation of p53 was significantly correlated to tumour size over 20 mm, negative oestrogen receptor (ER) status, DNA aneuploidy, high S-phase fraction and positive erbB-2 status. Cytoplasmic p53 was significantly correlated to distance recurrence-free survival in patients negative for nuclear p53 (P < 0.0001). Cellular p53 accumulation was an independent prognostic factor, in addition to lymph node status and ER content. We conclude that consideration of cytoplasmic staining enhances the clinical importance of p53.

Relationships of DNA ploidy, S-phase fraction and hormone receptor status to tumor stage in breast cancers detected by population screening. The South-East Sweden Breast Cancer Group.

Cellular DNA content was analyzed by flow cytometry and estrogen and progesterone receptors by an immuno-biochemical method (EIA) in a consecutive series of 807 frozen breast-cancer samples. Before the beginning of the study, a mammography screening program had been introduced in the region where the tumors were diagnosed. Forty percent of the tumors were judged as DNA diploid, of which 86% were ER-positive. The proportion of ER-positive tumors among non-diploids was significantly lower, or 73% (p less than 0.001). S-phase fraction (SPF) was estimated in 691 cases (86%), with an overall mean of 8.4%. DNA ploidy as well as ER and PR status were independently related to SPF. Unlike the results obtained in most older series, the biological variables correlated significantly with tumor staging factors such as lymph-node status and tumor size. Patients with nodal involvement, especially those with 4 positive nodes or more, more often had tumors which were receptor-negative, DNA aneuploid and of high S-phase rate. Large tumor size was significantly related to lower frequencies of receptor positivity and strongly related to DNA aneuploidy and high S-phase fraction. Multiple linear regression analysis showed that these relationships were mainly due to the associations of SPF with the other variables. S-phase fraction was the only independent factor predicting nodal status, while DNA ploidy in addition to SPF was associated with tumor size. In fact, DNA ploidy (p less than 0.001), ER and PR status (p less than 0.001, p = 0.002), nodal status (p = 0.04) and tumor size (p less than 0.001) were all independently related to SPF.

Interrelations between cellular DNA content, S-phase fraction, hormone receptor status and age in primary breast cancer. A series of 1,342 consecutively detected tumors. South-East Sweden Breast Cancer Group.

Estrogen and progesterone receptors were assessed by an immuno-biochemical method and DNA content was analysed by flow cytometry in a consecutive series of 1,342 frozen breast cancer samples. Forty-six percent of the ER-positive tumors were DNA diploid compared to 23% among ER-negative cases. The proportion of ER-/PR- cases was highest among hypertetraploid tumors (45%) and lowest among DNA diploids (13%). While receptor positivity and DNA ploidy were strongly related, no differences in mean receptor levels were detected when comparing DNA diploid and aneuploid cases of receptor positive tumors. In receptor positive tumors ER content--but not PR content--increased with age. S-phase fraction (SPF) was estimated in 1,165 cases (87%) with an overall mean of 8.6%. Tumors with high S-phase levels and DNA hypodiploid tumors were significantly more often found in younger than in older patients. The frequency of DNA hypodiploidy was less than 1% among women older than 75 years, while it was 8% among those aged 40 years or younger. S-phase fraction was inversely related to ER and PR status. However, while mean SPF gradually decreased with increasing levels of PR, no significant difference in S-phase fraction was seen for ER concentrations just above the cut-off level for receptor positivity. Tumors positive for both receptors showed the same pattern of DNA ploidy as ER+/PR- tumors while differences in S-phase fraction were observed between the groups. These results support that PR status better than ER status reflects hormone dependent growth in breast cancer.

p53 expression and the result of adjuvant therapy of breast cancer.

Functional p53 protein is essential for the cellular response to drug-induced DNA damage. We investigated p53 accumulation in tumour specimens from premenopausal breast cancer patients who were randomised to adjuvant chemotherapy (CMF) or postoperative radiotherapy. Of the tumours from 139 patients, 20 showed abnormal accumulation as judged with immunohistochemistry (> 10% positive tumour cells). The risk of distant recurrence was similar in the two treatment groups for patients whose primary tumours lacked p53 accumulation, whereas there was a significant benefit from CMF for patients showing abnormal accumulation (relative risk 0.18, 95% CI, 0.04-0.93). This result suggests that p53-dependent apoptosis is not a general mechanism by which breast cancer cells respond during CMF chemotherapy.

Intra- and inter-laboratory reproducibility of estrogen and progesterone receptor enzyme immunoassay in breast cancer cytosol samples--a Swedish multicenter study. Swedish Society of Cancer Study Group.

Estrogen and progesterone receptor analysis results were compared within and between six laboratories in Sweden using frozen breast cancer cytosol samples, and the same technique (enzyme immunoassay, Abbott Laboratories). The concordance in receptor status (positive vs. negative) was excellent (98.4% (571/580)). The discordant results were attributable to values near cut-off (n = 4) or outliers (n = 5), the latter probably being due to analytical errors. One laboratory reported significantly higher ER concentrations than the others; thus caution should be observed when comparing absolute values from different centers. For PgR there were similar differences between the laboratories. However, the intra- and inter-laboratory differences were small compared with the overall variability in ER and PgR content between different samples in a large database. The range of the median intra-laboratory coefficient of variation was 11-23% for ER and 12-19% for PgR, indicating that there is room for improvement in the quality of assay performance.