N. Wilking

Influence of prior and subsequent pregnancy on breast cancer prognosis.

PURPOSE AND METHODSnThe prognostic influence of pregnancies 5 years before (n = 173) and after (n = 50) breast cancer diagnosis was investigated in 2,119 women less than 50 years of age with a primary operable breast cancer. The main end point was distant metastasis. Univariate and multivariate analyses were performed using the Cox proportional hazards model. In the analyses of the effect of pregnancy after diagnosis of breast cancer, a Cox model with a time-dependent covariate was applied.nnnRESULTSnWomen with a pregnancy before diagnosis had slightly larger tumors than the control group. However, they did not differ with respect to nodal status and estrogen receptor (ER) status. There was no evidence that women with a pregnancy during the 5-year period preceding breast cancer diagnosis had a worse prognosis compared with women without pregnancy during the same period. Similarly, there was no evidence that women with a pregnancy after breast cancer diagnosis had a worse prognosis.nnnCONCLUSIONnThe hormonal changes associated with pregnancy thus seem to have little, if any, influence on the prognosis of breast cancer. In the present study, at least, there was no indication of a worse prognosis. In fact, the relative hazard for women who became pregnant after diagnosis of breast cancer in comparison with women without a subsequent pregnancy was 0.48 (P = .14), which suggested a possible decreased risk of distant dissemination.

Knowledge and understanding among cancer patients consenting to participate in clinical trials.

The aim of this study was to explore the fulfilment of the requirements of informed consent in patients participating in cancer clinical trials. All patients consenting to a phase II or III clinical trial during one year were included (n=325, 176 women, 54%). Data were collected by a questionnaire, Quality of Informed Consent. The response rate was 87%. High levels of knowledge (>80%) were found for items concerning voluntariness, randomisation, benefits for future patients, participation in a research trial, and the right to withdraw. Less than 50% responded correctly to items about risks associated with the trial, the unproven nature of the trial and issues about insurances. High levels of perceived understanding were reported. Despite high levels of knowledge and perceived understanding in the majority of elements of informed consent, improvements are warranted regarding knowledge about risks, the unproven nature of the treatment and the duration of treatment.

Hormone replacement therapy after breast cancer: 10 year follow up of the Stockholm randomised trial

BACKGROUNDnThe management of hormonal deficiency symptoms in breast cancer survivors is an unsolved problem. While hormone replacement therapy (HRT) may increase the risk of breast cancer in healthy women, its effects on recurrence is unclear. Observational studies have suggested decreased recurrence rates from HRT. The few clinical trials in this field have all been closed preterm.nnnMETHODSnThe Stockholm trial was started in 1997 and designed to minimise the dose of progestogen in the HRT arm. Disease-free women with a history of breast cancer were randomised to HRT (n=188) or no HRT (n=190). The trial was stopped in 2003 when another Swedish study (HABITS, the Hormonal Replacement After Breast Cancer - Is it Safe?) reported increased recurrence. However the Stockholm material showed no excess risk after 4 years of follow-up. A long term follow-up has now been performed.nnnFINDINGSnAfter 10.8 years of follow-up, there was no difference in new breast cancer events: 60 in the HRT group versus 48 among controls (hazard ratio (HR)=1.3; 95% confidence interval (CI)=0.9-1.9). Among women on HRT, 11 had local recurrence and 12 distant metastases versus 15 and 12 for the controls. There were 14 contra-lateral breast cancers in the HRT group and four in the control group (HR=3.6; 95% CI=1.2-10.9; p=0.013). No differences in mortality or new primary malignancies were found.nnnINTERPRETATIONnThe number of new events did not differ significantly between groups, in contrast to previous reports. The increased recurrence in HABITS has been attributed to higher progestogen exposure. As both trials were prematurely closed, data do not allow firm conclusions. Both studies found no increased mortality from breast cancer or other causes from HRT. Current guidelines typically consider HRT contraindicated in breast cancer survivors. Findings suggest that, in some women symptom relief may outweigh the potential risks of HRT.

Steroid Receptor Levels in Breast Cancer: Relationships with Age and menopausal status

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.

Tamoxifen and megestrol acetate for postmenopausal breast cancer: diverging effects on liver proteins, androgens, and glucocorticoids.

Aim: To compare the effects of tamoxifen and megestrol acetate on liver proteins, androgens, and glucocorticoids during adjuvant treatment for postmenopausal breast cancer.Methods: A subgroup of women within a large prospective multicenter trial were followed with blood sampling every 3 mo during 2 yr. Women were randomized to receive either continuous tamoxifen 40 mg/d or repeated sequential treatment with tamoxifen and megestrol acetate (MA) 160 mg/d.Results: We found profound and distinct differences between the two regimens. Tamoxifen increased steroid-binding proteins (SHBG and CBG) and suppressed circulating androgens and IGF-I. In contrast, the metabolic effects of tamoxifen were clearly antagonized by MA. There was a rise in IGF-I and marked suppression of steroid-binding proteins. Levels of free testosterone were reduced by 70%. MA also caused apparent adrenal suppression.Conclusion: The different effects on anabolic/catabolic balance and adrenal function may relate to certain clinical effects during treatment.

p53 expression in breast and endometrium during estrogen and tamoxifen treatment of surgically postmenopausal cynomolgus macaques

Estrogens are important for both normal cell growth and malignant proliferation in the mammary gland as well as in the endometrium. Tamoxifen is a non‐steroidal anti‐estrogen widely used in breast cancer treatment. In recent years reports have been made of an increased risk of endometrial carcinoma during tamoxifen treatment. We used surgically menopausal cynomolgus macaques to study proliferation and p53 expression during hormonal replacement therapy (HRT) and tamoxifen treatment. Animals were treated continuously for 35 months with either conjugated equine estrogens (CEE; n = 20); medroxyprogesterone acetate (MPA; n =17); the combination of CEE + MPA (n = 13) or tamoxifen (n = 17) for 35 months. We found an increased expression of p53 in normal breast and endometrial tissue linked to CEE but not tamoxifen treatment. In the breast alveoli there was an association between proliferation measured by morphometry and p53 expression in all groups. However, in the endometrium CEE induced significantly more p53 positivity than tamoxifen, 9/20 vs. 3/17 in glands and 9/19 vs. 0/17 in stroma, respectively. If indeed long‐term treatment with tamoxifen as in the present study could inactivate the tumor‐suppressive function of p53, endometrial cells might thereby become more susceptible to genetic lesions associated with carcinogenesis.

Hormone therapy and estrogen receptor expression in breast cancer

Postmenopausal hormone therapy (HT) may increase breast cancer risk and influence tumor characteristics. We investigated 321 postmenopausal women aged 50–65 years, with breast cancer, diagnosed and treated at Radiumhemmet, Karolinska Hospital, during 1993–1997. In women using HT (n =90) estrogen receptor concentration (ER) at diagnosis were lower than in non-users (n =135) (1.17 vs 1.70 fmol/µg; p <0.05). HT users also had a tendency to less multifocal (5 vs 12%) (p <0.05) and metastatic disease (5% vs 2%) however this was not statistically significant. The estrogen receptor expression is always considered in the judgement on hormone dependency and the clinical decision on adjuvant endocrine therapy. A suppression of ER during HT could tentatively influence the treatment decisions in breast cancer patients and maybe disregard patients from endocrine treatment.