Breast cancer screening and immigrant women-A scoping review of attendance, knowledge, barriers and facilitators.

AIM: The aim of this study was to summarize the latest research reports about immigrant women and attendance in breast cancer screening. DESIGN: Scoping review. METHODS: Literature searches were made in CINAHL, PubMed, Web of Science, Google Scholar, Oatd and Oalster. Twenty-three articles were included in the study. Data were analysed with inductive content analysis. RESULTS: Out of data four main categories were formed: attendance rates, incidence, barriers and facilitators, and knowledge and perception. The results show that attendance rates, barriers and facilitators for attendance, knowledge and experience of breast cancer and breast cancer screening differ between several factors such as the woman's migrant background, country of origin, religion, length of stay in the new home country and sociodemographic factors.

Early detection of breast cancer rectifies inequality of breast cancer outcomes.

OBJECTIVES: To explain apparent differences among mammography screening services in Sweden using individual data on participation in screening and with breast cancer-specific survival as an outcome. METHODS: We analysed breast cancer survival data from the Swedish Cancer Register on breast cancer cases from nine Swedish counties diagnosed in women eligible for screening. Data were available on 38,278 breast cancers diagnosed and 4312 breast cancer deaths. Survival to death from breast cancer was estimated using the Kaplan-Meier estimate, for all cases in each county, and separately for cases of women participating and not participating in their last invitation to screening. Formal statistical comparisons of survival were made using proportional hazards regression. RESULTS: All counties showed a reduction in the hazard of breast cancer death with participation in screening, but the reductions for individual counties varied substantially, ranging from 51% (95% confidence interval 46-55%) to 81% (95% confidence interval 74-85%). Survival rates in nonparticipating women ranged from 53% (95% confidence interval 40-65%) to 74% (95% confidence interval 72-77%), while the corresponding survival in women participating in screening varied from 80% (95% confidence interval 77-84%) to 86% (95% confidence interval 83-88%), a considerably narrower range. CONCLUSIONS: Differences among counties in the effect of screening on breast cancer outcomes were mainly due to variation in survival in women not participating in screening. Screening conferred similarly high survival rates in all counties. This indicates that the performance of screening services was similar across counties and that detection and treatment of breast cancer in early-stage reduces inequalities in breast cancer outcome.

Mammography screening reduces rates of advanced and fatal breast cancers: Results in 549,091 women.

BACKGROUND: It is of paramount importance to evaluate the impact of participation in organized mammography service screening independently from changes in breast cancer treatment. This can be done by measuring the incidence of fatal breast cancer, which is based on the date of diagnosis and not on the date of death. METHODS: Among 549,091 women, covering approximately 30% of the Swedish screening-eligible population, the authors calculated the incidence rates of 2473 breast cancers that were fatal within 10 years after diagnosis and the incidence rates of 9737 advanced breast cancers. Data regarding each breast cancer diagnosis and the cause and date of death of each breast cancer case were gathered from national Swedish registries. Tumor characteristics were collected from regional cancer centers. Aggregated data concerning invitation and participation were provided by Sectra Medical Systems AB. Incidence rates were analyzed using Poisson regression. RESULTS: Women who participated in mammography screening had a statistically significant 41% reduction in their risk of dying of breast cancer within 10 years (relative risk, 0.59; 95% CI, 0.51-0.68 [P < .001]) and a 25% reduction in the rate of advanced breast cancers (relative risk, 0.75; 95% CI, 0.66-0.84 [P < .001]). CONCLUSIONS: Substantial reductions in the incidence rate of breast cancers that were fatal within 10 years after diagnosis and in the advanced breast cancer rate were found in this contemporaneous comparison of women participating versus those not participating in screening. These benefits appeared to be independent of recent changes in treatment regimens.

A comprehensive tool for measuring mammographic density changes over time.

BACKGROUND: Mammographic density is a marker of breast cancer risk and diagnostics accuracy. Density change over time is a strong proxy for response to endocrine treatment and potentially a stronger predictor of breast cancer incidence. We developed STRATUS to analyse digital and analogue images and enable automated measurements of density changes over time. METHOD: Raw and processed images from the same mammogram were randomly sampled from 41,353 healthy women. Measurements from raw images (using FDA approved software iCAD) were used as templates for STRATUS to measure density on processed images through machine learning. A similar two-step design was used to train density measures in analogue images. Relative risks of breast cancer were estimated in three unique datasets. An alignment protocol was developed using images from 11,409 women to reduce non-biological variability in density change. The protocol was evaluated in 55,073 women having two regular mammography screens. Differences and variances in densities were compared before and after image alignment. RESULTS: The average relative risk of breast cancer in the three datasets was 1.6 [95% confidence interval (CI) 1.3-1.8] per standard deviation of percent mammographic density. The discrimination was AUC 0.62 (CI 0.60-0.64). The type of image did not significantly influence the risk associations. Alignment decreased the non-biological variability in density change and re-estimated the yearly overall percent density decrease from 1.5 to 0.9%, p < 0.001. CONCLUSIONS: The quality of STRATUS density measures was not influenced by mammogram type. The alignment protocol reduced the non-biological variability between images over time. STRATUS has the potential to become a useful tool for epidemiological studies and clinical follow-up.

A clinical model for identifying the short-term risk of breast cancer.

BACKGROUND: Most mammography screening programs are not individualized. To efficiently screen for breast cancer, the individual risk of the disease should be determined. We describe a model that could be used at most mammography screening units without adding substantial cost. METHODS: The study was based on the Karma cohort, which included 70,877 participants. Mammograms were collected up to 3 years following the baseline mammogram. A prediction protocol was developed using mammographic density, computer-aided detection of microcalcifications and masses, use of hormone replacement therapy (HRT), family history of breast cancer, menopausal status, age, and body mass index. Relative risks were calculated using conditional logistic regression. Absolute risks were calculated using the iCARE protocol. RESULTS: Comparing women at highest and lowest mammographic density yielded a fivefold higher risk of breast cancer for women at highest density. When adding microcalcifications and masses to the model, high-risk women had a nearly ninefold higher risk of breast cancer than those at lowest risk. In the full model, taking HRT use, family history of breast cancer, and menopausal status into consideration, the AUC reached 0.71. CONCLUSIONS: Measures of mammographic features and information on HRT use, family history of breast cancer, and menopausal status enabled early identification of women within the mammography screening program at such a high risk of breast cancer that additional examinations are warranted. In contrast, women at low risk could probably be screened less intensively.

Comparison of handheld ultrasound and automated breast ultrasound in women recalled after mammography screening.

Background Automated breast volume scanner (ABVS) is an ultrasound (US) device with a wide scanner that sweeps over a large area of the breast and the acquired transverse images are sent to a workstation for reconstruction and review. Whether ABVS is as reliable as handheld US is, however, still not established. Purpose To compare the sensitivity and specificity of ABVS to handheld breast US for detection of breast cancer, in the situation of recall after mammography screening. Material and Methods A total of 113 women, five with bilateral suspicious findings, undergoing handheld breast US due to a suspicious mammographic finding in screening, underwent additional ABVS. The methods were assessed for each breast and each detected lesion separately and classified into two categories: breasts with mammographic suspicion of malignancy and breasts with a negative mammogram. Results Twenty-six cancers were found in 25 women. In the category of breasts with a suspicious mammographic finding (n = 118), the sensitivity of both handheld US and ABVS was 88% (22/25). The specificity of handheld US was 93.5% (87/93) and ABVS was 89.2% (83/93). In the category of breasts with a negative mammography (n = 103), the sensitivity of handheld US and ABVS was 100% (1/1). The specificity of handheld US was 100% (102/102) and ABVS was 94.1% (96/102). Conclusion ABVS can potentially replace handheld US in the investigation of women recalled from mammography screening due to a suspicious finding. Due to the small size of our study population, further investigation with larger study populations is necessary before the implementation of such practice.

Adding 3D automated breast ultrasound to mammography screening in women with heterogeneously and extremely dense breasts: Report from a hospital-based, high-volume, single-center breast cancer screening program.

PURPOSE: The aim of this study was to evaluate the impact of the 3D automated breast ultrasound (3D ABUS) when added to full field digital screening mammography (FFDSM), on breast cancer detection and recall rates in asymptomatic women with dense breasts examined in a high-volume breast cancer screening mammography center. METHODS AND MATERIAL: 1668 asymptomatic women, age 40-74 years, with heterogeneously dense parenchyma (ACR3) or extremely dense breast (ACR4) were included in the study. FFDSM was performed using standard craniocaudal (CC) and mediolateral oblique (MLO) views followed by anteroposterior (AP); lateral (LAT) and medial (MED) acquisitions of 3D ABUS in both breasts. All mammograms were double read by two dedicated breast radiologists. The 3D ABUS was read by the first radiologist immediately after reading the mammograms. The second reader looked at the 3D ABUS only if there was a need for consensus discussion because of unclear or abnormal mammograms or 3D ABUS. RESULTS: The combined FFDSM and 3D ABUS generated a total of 6.6 cancers per 1000 women screened (95% CI: 3.0, 10.2; p<0.001) compared with 4.2 cancers per 1000 women screened (95% CI) for FFDSM alone. The difference in yield was an additional 2.4 detected cancers per 1000 women screened (95% CI: 0.6, 4.8; p<0.001). The corresponding recall rate per 1000 women screened was 13.8 (95% CI: 9.0, 19.8) for FFDSM alone and 22.8 for combined FFDSM and ABUS (95% CI: 16.2, 30.0), yielding a difference of an additional 9.0 recalls per 1000 women screened (95% CI: 3.0, 15.0; p=0.004). CONCLUSION: The addition of 3D ABUS to FFDSM in women with ACR3 or ACR4 breast density significantly improved invasive breast cancer detection rate with an acceptable recall increase.

A new method to gently place biopsy needles or treatment electrodes into tissues with high target precision.

We present a new core needle biopsy and treatment electrode precision placement technique which, regardless of needle size, target lesion hardness and elasticity, makes it possible to precisely place an image guided device inside the abnormal tissue. Once inside the abnormal lesion, multiple tissue samples can be collected using a dedicated trocar and collecting system. Our unique "Fourier" driver substitutes the commonly used spring-loaded device or complements the jerky insertion technique used by experienced interventional physicians. It enables the physician to precisely and with extreme tactility maneuver even large diameter core needles or treatment-electrodes into the lesion using only a diminutive external force. This is achieved by applying supporting servo-controlled mechanical high-acceleration micro-pulses, proportional to the average vector directed by the physician. The Fourier-needle or Fourier-electrode stands completely non-moving when the system automatically goes into full idling. This means that the angle of attack successively and arbitrary can be aligned to hit the target, becoming successively symmetrically inserted into even small tumors to be treated as well as exactly hit any point outlined by real time ultrasound guiding. This kind of biopsy needle or treatment electrode placement results in a uniquely accurate and less traumatic procedure. Due to the risk of disseminating viable tumor cells the precision placement device can be combined with a computer controlled anti-seeding system, denaturizing tumor cells detached during penetration of the biopsy needle or treatment electrode.

Contrast-enhanced ultrasound using real-time contrast harmonic imaging in invasive breast cancer: comparison of enhancement dynamics with three different doses of contrast agent.

BACKGROUND: In the last few years new potential applications have been developed for contrast-enhanced ultrasound (CEUS) and the management of breast diseases, but there is still some debate concerning the optimal dose to evaluate breast lesions, especially as a diagnostic tool. PURPOSE: To compare different CEUS doses of injected contrast agent in order to establish an optimal dose for the diagnosis of invasive breast cancer. MATERIAL AND METHODS: In Group A we compared the bolus dose of 1.2 mL vs. 2.4 mL and in Group B we compared the bolus dose of 2.4 mL vs. 4.8 mL (26 and 25 invasive carcinomas, respectively). CEUS was performed in real-time contrast harmonic imaging (CHI) using a L9-3 MHz probe. All examinations were recorded in a contrast side/side imaging mode loop for 120 s. Wash-in and wash-out patterns of the contrast agent were analyzed with advanced US quantification software and kinetic curves were used for statistical analysis. RESULTS: In Group B (2.4 mL vs. 4.8 mL), more and stronger correlation was found among kinetic parameters (area under the curve, P < 0.00001; lognormal model parameters, µ, P = 0.0007 and σ, P < 0.0001; mean transit time, P < 0.0001; model-based wash-out ratios, W21m, P = 0.0002; W50m, P = 0.0001; time-to-peak, P = 0.005) as compared to Group A (1.2 mL vs. 2.4 mL). CONCLUSION: The optimal way to evaluate kinetic features of invasive breast tumors using real-time CEUS is with an injection of contrast agent of either 2.4 mL or 4.8 mL.

Automated measurement of volumetric mammographic density: a tool for widespread breast cancer risk assessment.

INTRODUCTION: Mammographic density is a strong risk factor for breast cancer and an important determinant of screening sensitivity, but its clinical utility is hampered due to the lack of objective and automated measures. We evaluated the performance of a fully automated volumetric method (Volpara). METHODS: A prospective cohort study included 41,102 women attending mammography screening, of whom 206 were diagnosed with breast cancer after a median follow-up of 15.2 months. Percent and absolute dense volumes were estimated from raw digital mammograms. Genotyping was performed in a subset of the cohort (N = 2,122). We examined the agreement by side and view and compared density distributions across different mammography systems. We also studied associations with established density determinants and breast cancer risk. RESULTS: The method showed good agreement by side and view, and distributions of percent and absolute dense volume were similar across mammography systems. Volumetric density was positively associated with nulliparity, age at first birth, hormone use, benign breast disease, and family history of breast cancer, and negatively with age and postmenopausal status. Associations were also observed with rs10995190 in the ZNF365 gene (P < 1.0 × 10(-6)) and breast cancer risk [HR for the highest vs. lowest quartile, 2.93; 95% confidence interval, 1.73-4.96 and 1.63 (1.10-2.42) for percent and absolute dense volume, respectively]. CONCLUSIONS: In a high-throughput setting, Volpara performs well and in accordance with the behavior of established density measures. IMPACT: Automated measurement of volumetric mammographic density is a promising tool for widespread breast cancer risk assessment.

Minimally-invasive treatment of early stage breast cancer: a feasibility study using radiofrequency ablation under local anesthesia.

The objective of this study was to assess efficacy and safety of percutaneous ultrasound (US) guided preferential radiofrequency ablation (PRFA) in early breast carcinoma under local anesthesia and to evaluate a new assessment protocol. Eighteen breast cancer patients were enrolled in order to receive PRFA treatment three weeks prior to resection. Pain assessment was performed using the visual analoge scale. Analysis of treatment success was performed using magnetic resonance imaging (MRI) as well as histological assays for hematoxylin & eosin (H&E) and cytokeratine 8 (CK8). In a subset of patients contrast enhanced ultrasound (CEUS) was performed before and after treatment. MRI showed no residual tumor growth in 100% (18/18) of cases. Complete tumor devitalization was indicated in 83% (15/18) of patients as judged by H&E staining and in 89% (16/18) as judged by immunostaining for CK8. In 100% (18/18) at least one histologic method showed devitalization in the entire tumor. Treatment was well tolerated. Pain experienced during the procedure was mild. US-guided PRFA of small breast carcinoma is feasible under local anesthesia. MRI and CK8 have proven valuable additions to the RF breast tumor ablation protocol. CEUS shows potential as a modality for radiological follow-up.

Correlation of contrast-enhanced ultrasound kinetics with prognostic factors in invasive breast cancer.

OBJECTIVES: To correlate contrast-enhanced ultrasound (CEUS) kinetic parameters with traditional and molecular prognostic factors in invasive breast cancer. METHODS: Seventy-five invasive breast cancers were evaluated with contrast harmonic imaging after the injection of a bolus dose of 2.4 ml sulphur hexafluoride microbubble contrast agent. The lognormal function was used for quantitative analysis of kinetic data. These parameters correlated with traditional prognostic factors (tumour size, histological type, tumour grade, axillary lymph node status) and immunohistochemical biomarkers (ER, PR and HER2 status). RESULTS: Statistically significant correlation was found between time-to-peak and tumour grade (P value = 0.023), PR status (P value = 0.042) and axillary node status (P value = 0.025). Wash-out ratio, measured at 21 s was significantly associated with ER status (P value = 0.042) and PR status (P value = 0.026). CONCLUSIONS: Invasive breast carcinomas exhibiting earlier peak enhancement and faster elimination of microbubble contrast agent at CEUS are found to be associated with established predictors of poor prognosis.

Mass detection in reconstructed digital breast tomosynthesis volumes with a computer-aided detection system trained on 2D mammograms.

PURPOSE: To develop a computer-aided detection (CAD) system for masses in digital breast tomosynthesis (DBT) which can make use of an existing CAD system for detection of breast masses in full-field digital mammography (FFDM). This approach has the advantage that large digital screening databases that are becoming available can be used for training. DBT is currently not used for screening which makes it hard to obtain sufficient data for training. METHODS: The proposed CAD system is applied to reconstructed DBT volumes and consists of two stages. In the first stage, an existing 2D CAD system is applied to slabs composed of multiple DBT slices, after processing the slabs to a representation similar to that of the FFDM training data. In the second stage, the authors group detections obtained in the slabs that detect the same object and determine the 3D location of the grouped findings using one of three different approaches, including one that uses a set of features extracted from the DBT slabs. Experiments were conducted to determine performance of the CAD system, the optimal slab thickness for this approach and the best method to establish the 3D location. Experiments were performed using a database of 192 patients (752 DBT volumes). In 49 patients, one or more malignancies were present which were described as a mass, architectural distortion, or asymmetry. Free response receiver operating characteristic analysis and bootstrapping were used for statistical evaluation. RESULTS: Best performance was obtained when slab thickness was in the range of 1-2 cm. Using the feature based 3D localization procedure developed in the study, accurate 3D localization could be obtained in most cases. Case sensitivities of 80% and 90% were achieved at 0.35 and 0.99 false positives per volume, respectively. CONCLUSIONS: This study indicates that there may be a large benefit in using 2D mammograms for the development of CAD for DBT and that there is no need to exclusively limit development to DBT data.

Percutaneous estradiol/oral micronized progesterone has less-adverse effects and different gene regulations than oral conjugated equine estrogens/medroxyprogesterone acetate in the breasts of healthy women in vivo.

Gene expression analysis of healthy postmenopausal women in a prospective clinical study indicated that genes encoding for epithelial proliferation markers Ki-67 and progesterone receptor B mRNA are differentially expressed in women using hormone therapy (HT) with natural versus synthetic estrogens. Two 28-day cycles of daily estradiol (E2) gel 1.5 mg and oral micronized progesterone (P) 200 mg/day for the last 14 days of each cycle did not significantly increase breast epithelial proliferation (Ki-67 MIB-1 positive cells) at the cell level nor at the mRNA level (MKI-67 gene). A borderline significant beneficial reduction in anti-apoptotic protein bcl-2, favouring apoptosis, was also seen followed by a slight numeric decrease of its mRNA. By contrast, two 28-day cycles of daily oral conjugated equine estrogens (CEE) 0.625 mg and oral medroxyprogesterone acetate (MPA) 5 mg for the last 14 days of each cycle significantly increased proliferation at both the cell level and at the mRNA level, and significantly enhanced mammographic breast density, an important risk factor for breast cancer. In addition, CEE/MPA affected around 2,500 genes compared with just 600 affected by E2/P. These results suggest that HT with natural estrogens affects a much smaller number of genes and has less-adverse effects on the normal breast in vivo than conventional, synthetic therapy.

Differentiation between benign and malignant breast tumors using kinetic features of real-time harmonic contrast-enhanced ultrasound.

BACKGROUND: Contrast-enhanced ultrasound (CEUS) has gained interest because of its ability to gather vascular information in diverse organs. There is still a subject of debate concerning its value in breast lesions, especially as a differential diagnostic tool. PURPOSE: To investigate whether kinetic parameters of CEUS can differentiate between malignant and benign breast lesions. MATERIAL AND METHODS: We evaluated 75 malignant and 21 benign lesions in the breast or axilla. Contrast harmonic imaging (CHI) US was performed after the injection of a bolus dose of 2.4 mL of Sono Vue® (Bracco, Milano, Italy). The following parameters were calculated for kinetic analysis: initial slope, time to peak enhancement, wash-out ratios W(21) and W(50) (relative decrease in signal intensity from the peak enhancement to 21 s and 50 s, respectively). RESULTS: A significant difference was found between the benign and malignant lesions in time-to-peak (P value <0.05) and wash-out ratios W(21) (P value <0.001) and W(50) (P value <0.001). The mean time-to-peak was 9.3 s for malignant and 14.6 s for benign lesions. The mean signal drop from peak to signal intensity measured at 50 s was 85% for malignant and 66% for benign lesions. There was no difference in absolute values of peak signal intensity and initial slope. The most significant difference between standardized benign and malignant wash-out curves was found at 21 s but statistical significance was reached in the range of 14-50 s. CONCLUSION: Real-time CEUS can evolve into a new non-invasive option for differentiate malignant from benign breast lesions.

Two-view and single-view tomosynthesis versus full-field digital mammography: high-resolution X-ray imaging observer study.

PURPOSE: To compare the diagnostic accuracy of two-dimensional (2D) full-field digital mammography with that of two-view (mediolateral and craniocaudal) and single-view (mediolateral oblique) tomosynthesis in an observer study involving two institutions. MATERIALS AND METHODS: Ethical committee approval was obtained. All participating women gave informed consent. Two hundred twenty women (mean age, 56.3; range, 40-80 years) with breast density of 2-4 according to American College of Radiology criteria were recruited between November 2008 and September 2009 and underwent standard treatment plus tomosynthesis with a prototype photon-counting machine. After exclusion criteria were met, this resulted in a final test set of 130 women. Ten accredited readers classified the 130 cases (40 cancers, 24 benign lesions, and 66 normal images) using 2D mammography and two-view tomosynthesis. Another 10 readers reviewed the same cases using 2D mammography but single-view tomosynthesis. The multireader, multicase receiver operating characteristic (ROC) method was applied. The significance of the observed difference in accuracy between 2D mammography and tomosynthesis was calculated. RESULTS: For diagnostic accuracy, 2D mammography performed significantly worse than two-view tomosynthesis (average area under ROC curve [AUC] = 0.772 for 2D, AUC = 0.851 for tomosynthesis, P = .021). Significant differences were found for both masses and microcalcification (P = .037 and .049). The difference in AUC between the two modalities of -0.110 was significant (P = .03) only for the five readers with the least experience (<10 years of reading); with AUC of -0.047 for the five readers with 10 years or more experience (P = .25). No significant difference (P = .79) in reader performance was seen when 2D mammography (average AUC = 0.774) was compared with single-view tomosynthesis (average AUC = 0.775). CONCLUSION: Two-view tomosynthesis outperforms 2D mammography but only for readers with the least experience. The benefits were seen for both masses and microcalcification. No differences in classification accuracy was seen between and 2D mammography and single-view tomosynthesis.

Correlating locations in ipsilateral breast tomosynthesis views using an analytical hemispherical compression model.

To improve cancer detection in mammography, breast examinations usually consist of two views per breast. In order to combine information from both views, corresponding regions in the views need to be matched. In 3D digital breast tomosynthesis (DBT), this may be a difficult and time-consuming task for radiologists, because many slices have to be inspected individually. For multiview computer-aided detection (CAD) systems, matching corresponding regions is an essential step that needs to be automated. In this study, we developed an automatic method to quickly estimate corresponding locations in ipsilateral tomosynthesis views by applying a spatial transformation. First we match a model of a compressed breast to the tomosynthesis view containing a point of interest. Then we estimate the location of the corresponding point in the ipsilateral view by assuming that this model was decompressed, rotated and compressed again. In this study, we use a relatively simple, elastically deformable sphere model to obtain an analytical solution for the transformation in a given DBT case. We investigate three different methods to match the compression model to the data by using automatic segmentation of the pectoral muscle, breast tissue and nipple. For validation, we annotated 208 landmarks in both views of a total of 146 imaged breasts of 109 different patients and applied our method to each location. The best results are obtained by using the centre of gravity of the breast to define the central axis of the model, around which the breast is assumed to rotate between views. Results show a median 3D distance between the actual location and the estimated location of 14.6 mm, a good starting point for a registration method or a feature-based local search method to link suspicious regions in a multiview CAD system. Approximately half of the estimated locations are at most one slice away from the actual location, which makes the method useful as a mammographic workstation tool for radiologists to interactively find corresponding locations in ipsilateral tomosynthesis views.

Effects of percutaneous estradiol-oral progesterone versus oral conjugated equine estrogens-medroxyprogesterone acetate on breast cell proliferation and bcl-2 protein in healthy women.

In a prospective, randomized clinical study 77 women were assigned randomly to receive sequential hormone therapy with either conventional oral conjugated equine estrogens (0.625 mg) with the addition on 14 of the 28 days of oral medroxyprogesterone acetate (5 mg) or natural E(2) gel (1.5 mg) with oral micronized P (200 mg) on 14 of the 28 days of each cycle. Because oral conjugated equine estrogens-medroxyprogesterone acetate induced a highly significant increase in breast cell proliferation in contrast to percutaneous E(2)-oral P with a difference between therapies approaching significance, the former therapy has a marked impact on the breast whereas natural percutaneous E(2)-oral micronized P has not.