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p53 protein accumulation and gene mutation have been implicated in resistance to cytotoxic treatment. This study was performed to further assess the predictive value of p53 in breast cancer. Postmenopausal patients were randomized to adjuvant chemotherapy with cyclophosphamide, metothrexate, or 5-fluorouracil (CMF) vs. postoperative radiotherapy. The patients were also randomized to adjuvant tamoxifen vs. no endocrine treatment. Immunohistochemistry (IHC) and single-strand conformation polymorphism (SSCP), followed by direct sequencing, was performed. The p53 altered group, regarded as positive for p53 gene mutation and/or p53 protein accumulation, tended to benefit more from CMF than from radiotherapy as compared with others regarding distant recurrences. In the group lacking p53 alteration there was a significantly decreased local recurrence rate in the radiotherapy group as compared with the CMF group (RR = 0.24, 95% CI = 0.083 0.62), whereas no benefit from radiotherapy was found for patients showing p53 alterations. Tamoxifen significantly decreased the rate of distant recurrence for estrogen receptor-positive patients with no apparent difference in relation to p53 alteration. It is suggested that p53 alteration indicates benefit from CMF compared with radiotherapy regarding distant recurrence-free survival and the best local control with radiotherapy is achieved in the absence of p53 alteration. Finally, altered p53 status is probably not a marker of resistance to tamoxifen.

In an investigation by the Swedish Cancer Society, the present status, critical issues and future aspects and prospects were described by an expert group for each of nine major areas of radiation research. A summary of the investigation is presented in this report. A more extensive summary (in Swedish) can be found at www.Cancerfonden.se. It is concluded that radiation therapy plays an increasingly important role in curative and palliative tumour treatment and presents a considerable challenge to research. Several suggestions are made that could improve the possibilities for high-quality radiation therapy research in Sweden.

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.

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.

The paper presents descriptive data concerning relationships between age, menopausal status and steroid receptor content in primary breast carcinoma. The study was based on 2,329 women with primary breast carcinoma diagnosed in Stockholm county during 1980-1983. Oestrogen (ER) and progesterone receptor (PgR) content was determined using the isoelectric focusing technique. All analyses were done in one laboratory. There was a gradual increase in mean ER values with age. Premenopausal patients had lower mean ER values than peri- and postmenopausal patients of the same age. In contrast, PgR levels were similar in different age-groups. This could be a result of an insufficient stimulation of the tumour cells via the ER pathway. It is also possible that the PgR stimulation is maximal already at ER values below those found in old patients. It is concluded that steroid receptor content measured with commonly used ligand assays may reflect both biological properties of the tumour cells as well as influences by nontumoural factors, e.g. the endogenous levels of sex hormones.