Pregnancy postponement and childlessness leads to chronic hypervascularity of the breasts and cancer risk.

Epidemiologists have established that women with small families, and particularly nulliparae, are prone to develop breast cancer later in life. We report that physiological mammary hypervascularity may be an intermediate reason against the background that breast-core vascularity is normal in pregnancy but pathological in the vascularisation of cancer. We examined breast 'core' vascularity in nulliparae during their potential reproductive life and in parous women after their last birth but before their menopause. Fifty clinically normal pre-menopausal non-pregnant women (100 breasts) were studied daily for one 'luteal positive' menstrual cycle. Their parity history varied from zero to five babies. Under controlled domestic conditions each wore a special electronic thermometric bra to automatically record breast 'core' temperature changes as a measure of mammary tissue blood flow. In the nulliparae there was a rise of breast vascularity throughout reproductive life. In the parous women, a year or so after each birth, breast vascularity was reset at a lower level than before the pregnancy; thereafter, as in nulliparae, there was progressive increase in mammary vascularity until the menopause.

Meta-analysis of sequential luteal-cycle-associated changes in human breast tissue.

We chronobiologically estimate the time relations of physiological and morphological changes in breast tissue during the luteal phase of the menstrual cycle, as a cascade led by the progesterone peak. The timing and uncertainties of maxima in epithelial mitotic frequency, breast and epithelial volume, breast surface temperature, water content, blood flow and apoptosis are given as parts of a rhythmic element in a broader time structure or chronome.

Progesterone resistance in women who have had breast cancer.

OBJECTIVE: To investigate whether certain physiological responses to luteal progesterone are normal in women previously treated for breast cancer. DESIGN: Salivary progesterone concentrations, basal body temperatures, and breast blood flow changes (surface temperature method) were all recorded daily for one natural menstrual cycle. SETTING: Participants in the study made saliva collections and temperature measurements at home under semi-standardised conditions with supervisory visits by a project nurse. PARTICIPANTS: Twenty-five controls were compared with 30 women with previous breast cancer; all but three participants were parous and the average ages were 39 years (range 28-48) and 40 years (range 29-46), respectively. On average the women with previous breast cancer had had surgery 2.4 years previously; the operation was usually mastectomy, leaving the contralateral breast for study. RESULTS: Follicular phase (day 1-14) oral temperature averages were statistically indistinguishable between women in the control group and those with previous breast cancer. Luteal progesterone profiles were considered in the normal range for the controls and patients. However, the women with previous breast cancer, on average, exhibited a significantly smaller rise in the luteal phase basal body temperature. Follicular phase breast surface temperature was significantly higher in the breast cancer group (+0.30 degree C). This group showed a highly significant reduction of the luteal heat cycle in their breasts. CONCLUSIONS: Two progesterone-mediated physiological mechanisms have been found to be significantly less responsive in women with previous breast cancer than controls. The literature has been reviewed. Progesterone resistance could be a clinical entity and could be important in carcinogenesis.

Sir James Young Simpson Memorial Lecture 1995. Breast cancer prevention: a pathologist's approach.

Few would argue that there is not substantial room for an improvement in breast cancer practice. It has to be borne in mind that the United Kingdom experience in the 1980s was a 50:50 survival to death ratio in the 10 years after diagnosis. Preliminary analysis of the effects of mammographic screening suggests that there will be a real but small fall in overall mortality. Existing practice involves three stages: first, the 'earliest' detection of a lump by palpation or imaging; second, diagnosis by histopathology; and third, treatment by surgery, etc. Evidence is given that the limited success of existing practice could be due, in part, to a failure to recognize the precancerous state of the mammary tissue as a whole in cancer cases; and a failure to exploit this state for earlier diagnosis. In support of these contentions, comparative data from the microscopy of cancer-associated breasts and age-matched normal breast are given. There is a gross excess of focal hyperplasia in premenopausal cancer-associated breast tissue. Further, epidemiological data are consistent in that the tissue is subject to a sixfold increase in the risk of further primary carcinogenesis. A method is presented for detecting the cancer-associated breast. It exploits the breast menstrual cycle, a subject which is reviewed in extenso. Physiologically the premenopausal mammary tissue goes into a monthly pregnancy rehearsal with glandular proliferation and increased blood supply. The latter effects a luteal heat cycle, which can be measured readily by an electronic thermometric bra as increased breast surface temperature (1 degree C). Data are presented in terms of 50 normal breasts and 41 cancer-associated breasts studied daily (with progesterone assays) for one menstrual cycle. The cancer-associated breasts exhibit an absent or altered response to endogenous progesterone during the luteal phase of the menstrual cycle. The abnormality in the luteal heat cycle is maximal during the few days just after ovulation. Our data indicate that a 1-h clinical test at this time achieves a sensitivity of 71% and a specificity of 80% for "clinically normal' yet cancer-associated breast tissue. Such patients would be candidates for increased surveillance and chemoprevention.

The luteal heat cycle of the breast in disease.

Wearing a special thermometric brassiere, selected women self-measured their breast surface temperature. These measurements were made during one hour each evening at home for one menstrual cycle under standard conditions of overclothing and room temperature. To stage their cycle they also collected daily samples of saliva in their freezer for immuno-assay of progesterone concentration in the laboratory. A total of 82 women participated, most having young families. This total included four groups, a control group (N = 25) and three 'disease' groups, namely: family history of breast cancer (14); benign breast disease (12); and a 'cancer-associated' group (31) who had had previous cancer surgery. A significant breast temperature rhythm with a period at or about 28 days was found not only in the controls but also in the three groups of breasts designated 'disease'. Nevertheless, consistent rhythm abnormalities were found in all the disease groups. Most evident was a hyperthermia throughout the cycle, a reduction in the rhythm amplitude, and a tendency for the breast temperature rhythm to be manifest 1-2 days earlier in the menstrual cycle.

A non-invasive test for the pre-cancerous breast.

This paper describes a non-invasive, self-measured procedure by which the precancerous breast can be distinguished from the normal breast. The method involves wearing a specially designed thermometric brassiere for 90 min each evening at home through one menstrual cycle. Profiles of progesterone through the cycle, obtained from daily saliva sampling, and determination of the steroid content by radioimmunoassay, are made to allow the status and calendar date timing of the luteal phase to be established. Thus, cycles can be synchronised across subjects. In this study, two types of breast were compared: 50 normal breasts and 41 age-matched precancerous breasts. Differences between the groups were striking in terms of amplitude, phasing and average temperature during the luteal heat cycle. When these parameters and others were used as predictors in a linear discrimination and/or neural net analysis, a sensitivity and specificity of > 90% was achieved.

The luteal heat cycle of the breast in health.

Wearing a special thermometric brassiere, twenty-five normal women self-measured their breast surface temperature. The subjects averaged 39 years of age and all were parous. Observations were made for one hour each evening for one menstrual cycle under semi-standardized domestic conditions. They also collected daily samples of saliva for radioimmunoassay of progesterone concentration. The surface temperature of the breast is relatively cold around mid-cycle; thereafter, and without interruption in averaged data, the temperature increases steadily by about 1 degree C over the 12 days of the luteal phase; around the time of the menses, it falls rapidly. This heat rhythm does not occur in peri-menopausal low progesterone menstrual cycles or in patients where the breast tissue has been irradiated for cancer treatment.

A breast pre-cancer test? Preliminary results based on a breast temperature rhythm abnormality during the menstrual cycle.

This study documents the menstrual thermal cycle of 16 breasts considered at normal risk for breast (8 women) and 15 breasts considered at high risk for breast cancer (i.e. ipsilateral N = 7 or contralateral N = 8 to a previously [locally] excised carcinoma). The surface thermometry studies were carried out for 1 1/2 hours each evening for one menstrual cycle using a special automated instrumentation, the 'Chronobra', with the subject at home. The surface temperatures were adjusted to remove the fluctuations in arterial blood temperature during the menstrual cycle, so that they are thought to represent a breast-specific menstrual rhythm. Across subjects, the cycles were synchronised by the day of the progesterone peak obtained by radioimmunoassay of saliva collected daily. Following ovulation, the normal risk breasts exhibited a steady rise of temperature for 14 days to a well defined peak. In contrast the 'high-risk' breasts exhibited a continuous hyperthermia with smaller peaks. Linear discrimination analysis by multiple regression achieved a complete separation of the individual normal and 'high-risk' data sets. The method shows promise for the development of a non-invasive screening test for breast pre-cancer in premenopausal women.

The chronopathology of breast pre-cancer.

Breast temperatures have been measured by the automated instrumentation called the 'Chronobra' for 16 progesterone cycles in women at normal risk for breast cancer and for 15 cycles in women at high risk for breast cancer. Circatrigintan and circaseptan rhythm parameters have been examined by the single and population mean cosinor technique. In the first analysis there was strong evidence for a loss of the 28-day rhythm and its replacement by a 7-day rhythm (? frequency multiplication). In the more rigorous population mean cosinor method the presence of a phase and frequency synchronized rhythm with a period at or close to 28 days was sustained in the normal-risk subjects and it was confirmed that this rhythm is absent in the high-risk subjects. At tau = 7 days there was no rhythm detected in the normal-risk subjects and only a weak effect (p = 0.07) in the high-risk subjects. In other words, the circaseptan expression was detected in the high-risk breasts but then not in every case. The MESOR of the high-risk cases was highly significantly warmer than in the controls.

Genesis of breast cancer is in the premenopause.

In Britain and other high-risk countries, about a third of patients with breast cancer are premenopausal at diagnosis. In the remainder, tumour initiation might have occurred in the premenopause, even though the clinical presentation was late in life. This possibility has important implications for breast cancer prevention and screening. The relations between the patient's age and tumour kinetics, prognosis, oestrogen receptors, and environmental X-ray carcinogenesis were studied, together with the age-related protection afforded by pregnancy. The findings support the hypothesis that breast cancer is initiated in the premenopause.

Immunocytochemical demonstration and significance of p21 ras family oncogene product in benign and malignant breast disease.

It has been suggested that the immunocytochemical demonstration of the p21 ras oncogene product is a useful marker of malignancy in breast disease. We have studied the reactivity of a series of specimens of benign and malignant breast disease with the anti ras p21 monoclonal antibody Y13-259, and shown widespread positive staining in both benign and malignant (including metastatic) disease as well as in adjacent 'normal' epithelium. In addition some staining of stromal cells as well as nerve fibres was observed. Our results suggest that the presence of ras p21 protein as demonstrated by this antibody is not a useful marker of malignancy or of proliferating epithelium but is rather a normal feature of certain cell types.