The breast cancer continuum in hormone-receptor-positive breast cancer in postmenopausal women: evolving management options focusing on aromatase inhibitors.

There are now a number of highly effective options for the treatment of hormone-receptor-positive breast cancer. Although tamoxifen was the standard hormonal treatment for many years, we now have another option for postmenopausal women: the third-generation aromatase inhibitors (AIs) anastrozole, exemestane and letrozole. A number of trials have investigated the use of third-generation AIs compared with tamoxifen throughout the continuum of treatment settings for postmenopausal women with breast cancer. In the neoadjuvant setting, letrozole, given for 4 months, resulted in better overall clinical response and breast-conserving surgery rates than tamoxifen. The Immediate Preoperative Anastrozole Tamoxifen or Combined with Tamoxifen trial gave anastrozole for 3 months with no difference in clinical response but significantly improved breast-conserving surgery rates. Compared with tamoxifen, anastrozole and letrozole significantly improved disease-free survival as early adjuvant treatment for hormone-receptor-positive disease. Switching to anastrozole or exemestane after 2 to 3 years of adjuvant tamoxifen for a total of 5 years of therapy was also more effective than continued tamoxifen. All three agents are approved in the early adjuvant or switching setting in the USA. Letrozole following 5 years of tamoxifen as extended adjuvant treatment improved disease-free survival and, in the node-positive subgroup, overall survival when compared with placebo. Anastrozole and letrozole are both approved for the first-line treatment of hormone-sensitive advanced breast cancer in postmenopausal women; letrozole showed an improved response rate compared with tamoxifen. Anastrozole, letrozole and exemestane are all indicated for the second-line treatment of advanced breast cancer. In summary, third-generation AIs have been shown to have superior efficacy over tamoxifen in the metastatic, neoadjuvant and adjuvant settings and to improve outcome as extended adjuvant therapy following 5 years of tamoxifen. Ongoing studies will further define the role of sequential adjuvant treatment. Appropriate duration of treatment is another important area of investigation. This review will cover hormonal therapy for postmenopausal women with breast cancer and will not address the treatment of premenopausal women.     

Modelling the early detection of breast cancer.

A mathematical model was developed to predict the outcome of early detection clinical trials or programs targeted at evaluating mortality benefit from earlier diagnosis of breast cancer. The model was applied to eight randomized breast cancer trials, which were carried out to evaluate the benefits of mammography, physical examination or their combination. The model assumes that breast cancer is a progressive disease and any mortality benefit from earlier diagnosis is generated from a favorable shift in the stage at diagnosis relative to usual care. The model predicted the reduction in mortality for seven of the eight trials within the reported confidence intervals. Input data required by the models are: stage shift distribution, examination schedules, population age distribution, follow up time, and survival conditional on stage at diagnosis. Survival distributions were obtained from the 1973-82 SEER database whereas the remaining data was obtained for each of the trials. Information on sensitivity and stage was ordinarily available during the early phase of the trials. The theoretical model has the promise of being able to predict the long-term outcome of early detection trials or programs during the initial examination phase. The theoretical model is general and may be applied to other chronic diseases, which satisfy the basic assumptions.     

The impact of mammography on breast cancer detection

Background: Mammography has different effects on the epidemiologyof breast cancer, i.e., while increasing the registered incidenceit can reduce mortality. This study was aimed at obtaining quantitativeestimates of the impact of mammography on breast cancer detection. Subjects and methods: A case-control study was conducted inNorthern Italy between 1985 and 1991 on 2596 cases of histologicallyconfirmed breast cancer and 2005 controls in hospital for acutediseases unrelated to known or suspected risk factors for breastcancer. Results: 15.6% of the patients reported one screening mammographyand 9.7% two or more. The age-adjusted breast cancer diagnosisodds ratios (OR) were 1.3 (95% confidence interval, CI 1.1 to1.5) for one mammography and 2.0 (95% CI 1.6 to 2.6) for twoor more. When allowance was made for major identified potentialdistorting factors, the OR decreased to 1.0 (95% CI 0.8 to 1.2)for one, and 1.3 (95% CI 1.0 to 1.8) for two or more mammographies.In the age-adjusted analysis, the association between screeningmammography and breast cancer detection was apparently strongerfor younger and pre-menopausal women, among more educated womenand those with no history of benign breast disease or breastbiopsy, and among women who had first-degree relatives withhistories of breast cancer. Conclusions: Although the association between mammography andbreast cancer was largely explained by selective screening,confirming at the epidemiological level that the relationshipis incidental, the unadjusted ratios are of public health interest,since they give a measure of the role of mammography in breastcancer detection. breast neoplasms, epidemiology, incidence mammography, risks factors     

The immunocytochemical detection of axillary micrometastases in breast cancer.

The histological detection of tumour metastases in axillary lymph nodes from cases of breast carcinoma is of major prognostic significance, but may be difficult when metastases are of microscopic size. We have therefore investigated whether immunohistological techniques can increase the accuracy of metastasis detection in axillary lymph nodes. Forty-five cases of breast carcinoma were studied, in all of whom the axillary lymph nodes had been reported as free of metastases. Paraffin sections from these cases were stained by immunoenzymatic techniques, using monoclonal antibodies directed against human milk fat globule membrane antigen ("anti-EMA") and against epithelial intermediate filaments ("anti-keratin"). In 4/12 cases of lobular carcinoma and in 3/33 cases of ductal carcinoma, previously unsuspected micrometastases were revealed by immunohistological staining, representing an overall increase in detection rate of 15% (and of 33% for the lobular carcinoma cases). In addition to this group of 45 histologically "negative" biopsies, 12 samples were studied in which only a proportion of the nodes had been reported as containing tumour. In 5 of these cases immunostaining revealed previously undetected metastases. These findings suggest that immunohistological analysis may have a routine role to play in the staging of breast carcinoma. It is noted that the 15% increase in diagnostic accuracy achieved in the present study is comparable to the proportion of breast carcinoma patients in whom disseminated disease develops despite their axillary lymph nodes being reported as tumour-free at the time of surgery.     

Mammographic detection of breast cancer and preoperative needle localization.

Since its early clinical use during the 1960s, mammography has become a widely accepted screening method for breast cancer. Its utilization may be capable of diminishing mortality by 40%. Screening programs have been instituted, and their cost effectiveness depends on the locale and age of the population screened. Mass screening has resulted in large numbers of nonpalpable lesions being biopsied. Needle localization techniques allow for these to be performed with a minimal chance of missing the lesion, while removing only a small volume of breast tissue. Although most lesions biopsied will be benign, 20-30% of those excised at any institution should be malignant. Consultation with experienced mammographers may be desirable when recommending mammography-based biopsy. The rate of detection of malignancy is higher in women who have a prior history of ipsilateral or contralateral breast cancer.     

Mammographic detection of early breast cancer

For the discovery of minimal breast cancer with mammography, photos under appropriate conditions are required, and for the abnormal shadows in the breast, detailed readings of the shadows and photos on the spot under the sufficient pressure over the breast enable us to draw clearer pictures. It is desirable to examine micro-calcification to perform accurate biopsy and histopathology; with serial section of the specimen. Furthermore, it has become important for the diagnosis of lesion with galactography for nipple discharge to detect early breast cancer. Henceforth, the role of mammography among all graphic diagnosis will become greater for the discovery of early breast cancer.     

Biochemical detection of recurrent breast cancer

When clinically obvious recurrence develops in breast cancer patients, a large tumor burden is usually present. The development of biochemical techniques to detect recurrence may allow early diagnosis and therapeutic benefit. Reviewed in detail is the use of 10 biochemical parameters, as well as chest x-rays and physical examinations. Present data indicate that serial chest x-rays, physical examinations, liver enzymes, and CEA are the most sensitive means of detecting recurrence.     

NIR spectroscopic detection of breast cancer

Near infrared spectroscopy (NIRS) utilizes intrinsic optical absorption signals of blood, water, and lipid concentration available in the NIR window (600-1000 nm) as well as a developing array of extrinsic organic compounds to detect and localize cancer. This paper reviews optical cancer detection made possible through high tumor-tissue signal-to-noise ratio (SNR) and providing biochemical and physiological data in addition to those obtained via other methods. NIRS detects cancers in vivo through a combination of blood volume and oxygenation from measurements of oxy- and deoxy-hemoglobin giving signals of tumor angiogenesis and hypermetabolism. The Chance lab tends towards CW breast cancer systems using manually scannable detectors with calibrated low pressure tissue contact. These systems calculate angiogenesis and hypermetabolism by using a pair of wavelengths and referencing the mirror image position of the contralateral breast to achieve high ROC/AUC. Time domain and frequency domain spectroscopy were also used to study similar intrinsic breast tumor characteristics such as high blood volume. Other NIRS metrics are water-fat ratio and the optical scattering coefficient. An extrinsic FDA approved dye, ICG, has been used to measure blood pooling with extravasation, similar to Gadolinium in MRI. A key future development in NIRS will be new Molecular Beacons targeting cancers and fluorescing in the NIR window to enhance in vivo tumor-tissue ratios and to afford biochemical specificity with the potential for effective photodynamic anti-cancer therapies.     

Improving early breast cancer detection: focus on methylation

The need for additional breast cancer screening tools is indisputably high, as one may conclude from the high rate of interval malignancies in women undergoing regular screening. DNA promoter methylation frequently occurs during breast carcinogenesis and is an early event in this process. Moreover, a field defect for methylation has been described and methylation values can reliably be assessed in limited amounts of DNA. Simultaneous detection of methylation of a panel of genes in breast fluids and/or blood derivatives could be both sufficiently specific and sensitive to be of additive value to current imaging-based screening methods. This review describes the recent developments in methylation detection in breast fluids, serum and plasma that paved the way for large prospective studies. These studies will provide us with the definite answer as to what will be the additive value of defining the methylation status of specific genes to current imaging-based screening methods.     

Early detection, epidemiology, and prevention of breast cancer.

Control of breast cancer will ultimately be achieved through a better understanding of the epidemiology of the disease and application of primary prevention. Until then, use of screening mammography offers the promise of a 30% reduction in breast cancer mortality, which continues to be shown by screening studies with prolonged follow-up. Biologic markers of cancer risk, including nipple aspirates and cyst fluid, suggest that a complete risk profile can be developed using fluid and tissue obtained from the normal breast. Epidemiologic studies of dietary factors and geographic differences in breast cancer risk continue to provide promising leads relating to the etiology of the disease. Increasing evidence suggests that circulating androgens and estrogens affect breast cancer risk, whereas exogenous estrogen therapy does not increase risk except for small subgroups of women at risk. Increasing understanding of the genetics of breast cancer will have an impact on the disease in the near future. The greatest impact in the short term will come from the use of tamoxifen for primary prevention of breast cancer. The retinoids, particularly N-(4-hydroxyphenyl)retinamide, hold great promise as agents for primary prevention.     

Epidemiology, prevention, and early detection of breast cancer.

Globally, breast cancer is the third most common form of cancer and the most common among women. The age-adjusted incidence rates of breast cancer are 176% higher in developed than in developing nations. Male breast cancer is rare, but important studies provided risk factor information for comparison with studies of female breast cancer. There has been considerable interest in a possible role of organochlorines and polychlorinated biphenyls in the etiology of breast cancer, but the results of several null studies indicate the likelihood of such associations is extremely remote, providing reassuring news for the public. Prophylactic mastectomy was observed to significantly reduce a woman's chances of developing breast cancer, but it does not lower the risk to zero. Tamoxifen was found to be an effective chemopreventive agent in the Breast Cancer Prevention Trial, but this result was not replicated in two randomized trials in Europe. Striking reductions in the risk for breast cancer were observed for raloxifene in a randomized, placebo-controlled trial that had been designed for the prevention of osteoporosis. A large-scale, randomized trial of tamoxifen-verus-raloxifene among women at increased risk for developing breast cancer is now underway.     

Casein and alpha-lactalbumin detection in breast cancer cells by immunocytochemistry.

Casein and alpha-lactalbumin are characteristic proteins produced by normal mammary cells under hormonal stimulation. Specific antisera were used to immunochemically stain for these two proteins in the unstimulated R3230AC transplantable rat mammary tumor as well as in normal lactating rat mammary tissue. Specific staining was observed in the lactating rat alveolar epithelial cells and in the cells lining the intraalveolar ducts with both antisera. In the R3230AC tumor some cells were shown to contain casein or alpha-lactalbumin; the majority of the tumor cells were unstained. These findings indicate that normal mammary cells as well as a small population of cells within the R3230AC tumor are actively synthesizing casein or alpha-lactalbumin. Furthermore, the results suggest that immunocytochemistry may be used to determine the functional heterogeneity of mammary tumors directly.     

Role of cancer thermography for detection of breast cancer

Out of one hundred and sixty-two patients that examined by contact thermography, forty-five cases involving 55 cancers were assessed for malignancy. The sensitivity and the specificity of this method of testing were 81.5% and 83.5%, respectively. False negative cases included early stage, small sized and papillotubular carcinomas. Twenty-five per cent of the fibroadenoma and mastopathy cases showed false positive findings. Further, half of the phyllodes tumor and mastitis cases also showed false positive findings. Two of six T0, Tis cases (33.3%) were diagnosed as malignant tumors by thermography. Contact thermographic examinations will be more widely used in the near future.