Therapeutic treatment of DMBA-induced mammary tumors with PPAR ligands.

The objective of this study was to evaluate the ability of troglitazone (a thiazolidinedione) and Wy-14,643 (a clofibrate) to inhibit progression of non-detectable and detectable mammary tumors in rats induced by 7,12 dimethylbenz(a)anthracene (DMBA) when compared to those receiving no treatment or tamoxifen. Although not as effective as tamoxifen in decreasing overall tumor incidence, Wy-14,643 reduced the percentage and number of malignant tumors that developed when compared to both troglitazone and control. Treatment of detectable tumors with either Wy-14,643 or troglitazone induced regression or stasis of total tumor volume in 40-50% of the animals, compared to only 10% in control and 65% in tamoxifen treated animals. Moreover, each PPAR ligand was as effective as tamoxifen in preventing additional tumor development. In summary, both PPAR ligands were more effective than no treatment in preventing tumor progression once detected. However, only the PPAR-alpha activator, Wy-14,643 was able to reduce the development of malignant tumors when administered prior to detection.

Positive predictive value of the Breast Imaging Reporting and Data System.

BACKGROUND: The American College of Radiology has established guidelines for outcomes monitoring known as the Breast Imaging Reporting and Data System (BIRADS). These recommendations include calculation of positive predictive values (PPV) and tracking of both benign and malignant histology. We collected this data for 688 radiographically guided biopsies and organized it according to the BIRADS assessment categories. The objective was to evaluate the contribution of the BIRAD System when used to stratify PPV, histology, and biopsy modality data according to the overall assessment rating. STUDY DESIGN: This study included data from 688 image-guided biopsies. Mammographic studies were either assigned a BIRADS rating at the time of examination or, if the image was taken before our use of BIRADS, examined retrospectively and rated. In these retrospective cases, the histologic outcomes of the biopsy remained unknown to the radiologist until ratings were assigned. Positive predictive value was calculated for each BIRADS category. RESULTS: The overall PPV for the sample was 0.23. The PPVs increased with increasing level of suspicion as follows: category 1 (0.0), category 2 (0.04), category 3 (0.03), category 4 (0.23), category 5 (0.92). Category 1 lesions represented 0.1% of the biopsies; category 2, 3.6%; category 3, 46.8%; category 4, 34.0%; and category 5, 15.4%. The most common histologic diagnoses of benign lesions biopsied were fibroadenoma and fibrocystic changes-proliferative and nonproliferative. The most common histologic diagnoses of malignant lesions biopsied were infiltrating ductal carcinoma and ductal carcinoma in situ. Utilization rates of the biopsy techniques varied by BIRADS category. CONCLUSIONS: Our study revealed that BIRADS does improve the quality of the risk assessment information by making the PPV more specific to a patient's mammogram rather than simply related to an overall PPV. Our histology analysis showed category 3 and category 4 benign biopsies were predominantly because of fibrocystic changes. Category 5 lesions were predominantly invasive ductal carcinoma. Analysis of biopsy modalities indicated the preferred method for management of radiographically detected lesions evolved from stereotactic core biopsy to directional, vacuum-assisted biopsy over the course of the study.

Prevention of rat mammary carcinoma utilizing leuprolide as an equivalent to oophorectomy.

A clinical trial is currently under way to examine the effectiveness of leuprolide as a breast cancer chemopreventive agent and contraceptive. This trial, as well as similar proposed studies, is based on the assumption that leuprolide is as effective as surgical castration in preventing the onset of mammary tumors; however, this has not been well documented in the DMBA animal model. We directly compared leuprolide and oophorectomy in this model and examined a combined therapy of leuprolide/bromocriptine. Twenty-seven day old female Sprague-Dawley rats were randomly allocated into one of eight groups. All rats received a 20-mg dose of DMBA at the age of 55 days. Group 1 (n = 10), no treatment; Group 2 (n = 9), leuprolide (100 microg/kg/day) for eight weeks beginning four weeks prior to DMBA; Group 3 (n = 10), oophorectomy four weeks prior to DMBA with replacement estrogen beginning four weeks following DMBA. Estrogen replacement was achieved with a 0.05-mg estradiol tablet releasing 0.833 microg/day over a 60-day period. Group 4 (n = 10), leuprolide (100 microg/kg/day) initiated two weeks prior to DMBA and continuing for two weeks following DMBA; Group 5 (n = 9), oophorectomy two weeks prior to DMBA with 0.05 mg of estradiol in depot form, releasing 0.833 microg/day, beginning four weeks following DMBA and continuing until week 16 of the study; Group 6 (n = 10), leuprolide (100 microg/kg/day) beginning two weeks prior to DMBA and continuing for the duration of the experiment; Group 7 (n = 10), leuprolide (100 microg/kg/day) for eight weeks beginning two weeks prior to DMBA; Group 8 (n = 9), leuprolide (100 microg/kg/day) and bromocriptine (83 microg/day) for eight weeks beginning two weeks prior to DMBA. At nineteen weeks (15 weeks post DMBA), animals were sacrificed and autopsies performed. One hundred percent of untreated animals developed tumors. No animals undergoing oophorectomy four weeks prior to DMBA or receiving leuprolide four weeks prior to and simultaneously with DMBA developed tumors. In animals pretreated two weeks prior to DMBA with leuprolide or oophorectomy, each group had one animal with tumor development. No tumors developed in the animals receiving ongoing injections of leuprolide. However, one tumor developed in those receiving leuprolide for the first eight weeks beginning two weeks prior to DMBA administration. One animal receiving both leuprolide and bromocriptine developed one tumor. We conclude that chemical oophorectomy (with leuprolide) is as effective as surgical oophorectomy in inhibiting DMBA induced carcinogenesis.

Prevention of DMBA-induced rat mammary carcinomas comparing leuprolide, oophorectomy, and tamoxifen.

Leuprolide, a gonadotropin releasing hormone agonist, is currently being evaluated in a pilot study of premenopausal women for the prevention of breast cancer. However, little data is available regarding the efficacy of leuprolide in experimental animal models of carcinoma when administered prior to the carcinogen. In the present study the capacity of leuprolide to prevent tumor development was evaluated by comparing its pretreatment effects in the DMBA-induced rat mammary carcinoma model to pretreatment with tamoxifen and oophorectomy. Fifty-five day old, female Sprague-Dawley rats were randomly allocated to one of four groups: 1) no treatment; 2) oophorectomy two weeks prior to DMBA; 3) leuprolide, 40 microg/kg/day; and 4) tamoxifen, 10 mg/kg/week. All animals received four 5 mg doses of DMBA for a total dose of 20 mg. Leuprolide and tamoxifen treatments began two weeks prior to DMBA and ended one week after DMBA administration. Animals were assessed weekly to determine palpable tumor onset, number, size, and volume. At the conclusion of the study (16 weeks), autopsies were performed and tumor tissue was collected for confirmation of malignancy. Seventy-eight percent of the untreated rats developed tumors. No tumors developed in the oophorectomy group, while the number of rats with tumors was significantly reduced (p<0.05) with both leuprolide (30%) and tamoxifen (21.9%) compared to controls (77.8%). There were no significant differences in the tumor number for each tumor-bearing rat or in tumor volume between treated and control groups. Using our dosage regimen, 'chemical oophorectomy' with leuprolide was not as effective as surgical oophorectomy in the prevention of chemical carcinogenesis by DMBA but was comparable to the results obtained with tamoxifen.

Expression of peroxisome proliferator activated receptor mRNA in normal and tumorigenic rodent mammary glands.

The peroxisome proliferator activated receptors (PPARs) alpha, beta/delta, and gamma are novel nuclear hormone receptors activated by long chain fatty acids and synthetic ligands and which regulate lipid metabolism. Recent studies have detected PPARgamma mRNA in human mammary tumor cell lines. The current study examined the expression profile of PPAR mRNAs in normal and malignant rodent mammary tissues. Virgin murine mammary glands contained PPAR alpha, beta/delta, and gamma mRNAs based on northern blot analysis. The PPARgamma isoform was predominantly gamma2 based on quantitative PCR analysis. During pregnancy and lactation, the PPARalpha and gamma mRNAs decreased while the PPAR beta/delta mRNA remained relatively unchanged. NMuMG cells, an epithelial line derived from normal murine mammary gland, expressed PPAR alpha, beta/delta, and gamma mRNAs, independent of the presence or absence of compounds modifying PPAR activity. In rats, the physiologic expression pattern of PPARgamma mRNA paralleled the murine model; levels were detected in virgin but not lactating mammary glands. In addition, the PPARgamma mRNA was not detected in several histologically distinct 7,12-dimethylbenz(a)anthracene induced mammary tumors. These findings suggest that PPARs may regulate mammary epithelial and stromal cell function in response to physiologic or pathologic stimuli that profoundly alter lipid metabolism.

Establishing a histologic basis for false-negative mammograms.

In order to explore the histology of false-negative mammograms, 264 consecutive patients with breast cancer were retrospectively reviewed until 100 patients with palpable cancers were identified. These patients were imaged by a dedicated mammographer within 6 months prior to biopsy. Nine of the 100 patients had "negative" readings originally, with 6 of the 9 still regarded as negative when re-examined after full knowledge of the tumor location. Histologic review of these six tumors showed a diffusely infiltrative pattern in five patients (three with invasive lobular carcinomas and two with multifocal, invasive ductal carcinomas). Although background breast density always serves in a critical relationship with tumor density on film, only one of these six patients showed a severe degree of mammographic breast density. Diffuse histology should be recognized as a principal cause of false-negative mammograms. Since mammography is based solely on anatomic contrasts, diffuse histology could easily prevent the perfection of this modality, calling attention to the need for improved adjunct imaging techniques.