Multimodal Breast Cancer Research Articles

Breast Cancer Clinical Trials: Past Half Century Moving Forward Advancing Patient Outcomes.

Clinical trials in breast cancer have contributed immensely to the advancements of modern multimodal breast cancer treatment. Due to improved screening methods and more effective biologic-based tailored systemic therapies, the extent of surgery necessary for local and systemic control of disease is decreasing. Sequential trials for ductal carcinoma in situ (DCIS) have changed the management of this disease and are culminating in randomized active surveillance studies in an effort potentially to prevent overtreatment of low- and intermediate-grade disease. For patients with initial node-positive disease, clipping and marking of the biopsy-proven nodal metastases before the start of neoadjuvant chemotherapy can allow for selective node dissection based on the axillary response. With the current advances in primary systemic therapy, feasibility trials are beginning to investigate the potential of nonoperative therapy for invasive cancers with percutaneously documented pathologic complete response. This article presents a review and update on landmark clinical trials related to DCIS, the extent of axillary surgery in node-positive disease, and the integration of systemic therapy with local therapy.

Adherence to the breast cancer surveillance program for women at risk for familial breast and ovarian cancer versus overscreening: a monocenter study in Germany.

Breast cancer (BC) is the leading cancer among women worldwide and in 5-10% of cases is of hereditary origin, mainly due to BRCA1/2 mutations. Therefore, the German Consortium for Familial Breast and Ovarian Cancer (HBOC) with its 15 specialized academic centers offers families at high risk for familial/hereditary cancer a multimodal breast cancer surveillance program (MBCS) with regular breast MRI, mammography, ultrasound, and palpation. So far, we know a lot about the psychological effects of genetic testing, but we know little about risk-correlated adherence to MBCS or prophylactic surgery over time. The aim of this study was to investigate counselees' adherence to recommendations for MBCS in order to adjust the care supply and define predictors for incompliance. All counselees, who attended HBOC consultation at the University Hospital Heidelberg between July 01, 2009 and July 01, 2011 were eligible to participate. A tripartite questionnaire containing sociodemographic information, psychological parameters, behavioral questions, and medical data collection from the German consortium were used. A high participation rate was achieved among the study population, with 72% returning the questionnaire. This study showed a rate of 59% of full-adherers to the MBCS. Significant predictors for partial or full adherence were having children (p=0.0221), younger daughters (p=0.01795), a higher awareness of the topic HBOC (p=0.01795, p<0.0001), a higher perceived breast cancer risk (p<0.0001), and worries (p=0.0008)/impairment (p=0.0257) by it. Although the current data suggest a good adherence of MBCS, prospective studies are needed to understand counselees' needs to further improve surveillance programs and adherence to them. Adherence to the breast cancer surveillance program for women at risk for familial breast and ovarian cancer versus overscreening-a monocenter study in Germany.

Cardiac Function After Multimodal Breast Cancer Therapy Assessed With Functional Magnetic Resonance Imaging and Echocardiography Imaging

Breast intensity modulated radiation therapy (IMRT) reduces high-dose heart volumes but increases low-dose volumes. We prospectively assessed heart changes after 3D conformal RT (3DCRT) and IMRT for left-sided breast cancer. Heart dose was analyzed individually, 3DCRT patients were moderately exposed, and IMRT was performed only in patients with unacceptably high heart doses upon 3DCRT planning. In 49 patients (38 patients received 3DCRT; 11 patients received IMRT; and 20 patients received neoadjuvant or adjuvant chemotherapy) magnetic resonance imaging (MRI) and echocardiography were performed before and at 6, 12, and 24 months after treatment. Mean heart dose for IMRT was 12.9 ± 3.9 Gy versus 4.5 ± 2.4 Gy for 3DCRT. Heart volumes receiving >40 Gy were 2.6% (3DCRT) versus 1.3% (IMRT); doses were >50 Gy only with 3DCRT. Temporary ejection fraction (EF) decrease was observed on MRI after 6 months (63%-59%, P=.005) resolving at 24 months. Only 3 patients had pronounced largely transient changes of EF and left ventricular enddiastolic diameter (LVEDD). Mitral (M) and tricuspid (T) annular plane systolic excursion (MAPSE and TAPSE) were reduced over the whole cohort (still within normal range). After 24 months left ventricular remodeling index decreased in patients receiving chemotherapy (0.80 vs 0.70, P=.028). Neither wall motion abnormalities nor late enhancements were found. On echocardiography, in addition to EF findings that were similar to those on MRI, global strain was unchanged over the whole cohort at 24 months after a transient decrease at 6 and 12 months. Longitudinal strain decreased in the whole cohort after 24 months in some segments, whereas it increased in others. Until 24 months after risk-adapted modern multimodal adjuvant therapy, only subclinical cardiac changes were observed in both 3DCRT patients with inclusion of small to moderate amounts of heart volume in RT tangents and in the patients treated with IMRT and reduced high-dose heart exposure.

Risikoadaptierte Früherkennung

Breast cancer surveillance programs for the general population are not adequate for the small number of women with hereditary breast and ovarian cancer syndrome. Breast cancer screening for women in Germany starts at the age of 50 years, but nearly half of all women with familial risk are already diagnosed with breast cancer at that time. Moreover, mammography alone is not suitable for an early diagnosis of breast cancer in young women from high-risk families. Their typical dense breast tissue causes a high rate of false-negative cases. Therefore, national and international prospective clinical trials were initiated to offer a multimodal breast cancer surveillance program including magnetic resonance tomography for the breast and semi-annual screening intervals to women with BRCA1/2 mutations and those from high-risk families who tested negative for BRCA1/2 mutations. This program will currently be evaluated by the 15 centers of the German Consortium for Hereditary Breast and Ovarian Cancer.

Simulation of mammographic breast compression in 3D MR images using ICP-based B-spline deformation for multimodality breast cancer diagnosis

Multimodality mammography using conventional 2D mammography and dynamic contrast-enhanced 3D magnetic resonance imaging (DCE-MRI) is frequently performed for breast cancer detection and diagnosis. Combination of both imaging modalities requires superimposition of corresponding structures in mammograms and MR images. This task is challenging due to large differences in (1) dimensionality and spatial resolution, (2) variations in tissue contrast, as well as (3) differences in breast orientation and deformation during the image acquisition. A new method for multimodality breast image registration was developed and tested. Combined diagnosis of mammograms and MRI datasets was achieved by simulation of mammographic breast compression to overcome large differences in breast deformation. Surface information was extracted from the 3D MR image, and back-projection of the 2D breast contour in the mammogram was done. B-spline-based 3D/3D surface-based registration was then used to approximate mammographic breast compression. This breast deformation simulation was performed on 14 MRI datasets with 19 corresponding mammograms. The results were evaluated by comparison with distances between corresponding structures identified by an expert observer. The evaluation revealed an average distance of 6.46 mm between corresponding structures, when an optimized initial alignment between both image datasets is performed. Without the optimization, the accuracy is 9.12 mm. A new surface-based method that approximates the mammographic deformation due to breast compression without using a specific complex model needed for finite-element-based methods was developed and tested with favorable results. The simulated compression can serve as foundation for a point-to-line correspondence between 2D mammograms and 3D MR image data.

Abstract 3051: The miR-200 family as a potential therapeutic target in inflammatory breast cancer.

Abstract Purpose: Inflammatory breast cancer (IBC) is the most lethal, aggressive variant of breast cancer characterized by rapid progression, local and distant metastases, younger age of onset, and poor overall survival. Despite advances in multimodal breast cancer care, no IBC specific therapy is available clinically, demonstrating a critical need to identify novel therapeutics that target the distinct biology of IBC. MicroRNAs (miRNAs) are small noncoding RNAs that regulate gene expression and have been implicated as potential therapeutic targets. Although the oncogenic or tumor-suppressor functions of a large number of miRNAs have been described in various solid tumors including breast cancer, the role of miRNAs in the biology of IBC is poorly understood. Herein, we investigated miRNAs differentially expressed in IBC, particularly miR-200 family miRNAs as potential therapeutic targets in IBC. Methods: MicroRNA microarray profiling was conducted in IBC and non-IBC cell lines, and microarray results were validated using qRT-PCR. MirZip lentiviral based mirRNA inhibition was used to stably knockdown miRNAs and the effects of specific miRNA knockdown on proliferation, EMT, colony and mammosphere formation was evaluated. For tumor progression and metastasis in vivo experiments, we injected 500,000 SUM149 miR-200a, miR-141 knockdown and control (N=15 for each group) cells into the cleared mammary fatpad of SCID/Beige mice. We also validated the expression of miR-200 miRNAs in IBC patient samples. Results: Differential expression of mirRNAs was observed in IBC vs. non-IBC cell lines with a significantly higher expression of all miR-200 family (miR-200a, miR-200b, miR-200c, miR-141 and miR-479) in IBC cell lines. These results were validated using qRT-PCR, with the IBC cell lines showing a &amp;gt;1,000-fold higher expression of miR-200s vs non-IBC aggressive cell lines (P&amp;lt;0.0001). Moreover, two known targets of the miR-200 family, Zeb1 and Zeb2, were significantly downregulated while E-cadherin was upregulated in the IBC samples. Importantly, these observations were validated in IBC patient samples which showed a significantly higher expression of all miRNA 200s compared to the normal breast tissues (P&amp;lt;0.001). In vitro, miR-200a and miR-141 knockdown significantly reduced both colony and mammosphere formation in the triple negative SUM149 cells (P&amp;lt;0.001) but did not have a significant effect on the HER2+ IBC cell lines SUM190 and MDA-IBC-3 (P&amp;gt;0.05) while it upregulated the EMT markers N-cadherin, Fibronectin, TGFβ, and Smad4 and reduced E-cadherin expression compared to transduced controls. In vivo, miR-200 knockdown resulted in an increase in tumor progression vs. controls (P&amp;lt;0.05, Day 63) while metastasis studies are undergoing. Conclusions: These data suggest that miR-200 family microRNAs play an important role in IBC tumor progression and altering miR-200 levels could be an efficacious approach to target IBC. Citation Format: Bisrat G. Debeb, Lara Lacerda, Richard Larson, Li Li, Wei Xu, Lei Huo, Caimiao Wei, Savitri Krishnamurthy, James Reuben, Naoto Ueno, Thomas Buchholz, Wendy A. Woodward, Morgan Welch Inflammatory Breast Cancer Research Program and Clinic. The miR-200 family as a potential therapeutic target in inflammatory breast cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3051. doi:10.1158/1538-7445.AM2013-3051

The Need for Lymph Node Dissection in Nonmetastatic Breast Cancer

Determining whether cancer has spread to locoregional lymph nodes is a critical step in the initial staging of breast cancer patients. Although axillary dissection reliably identifies nodal metastases and prevents the recurrence of cancer in the axilla, there is a significant incidence of long-term side effects, notably lymphedema, and the procedure is of no therapeutic benefit in women without axillary metastases. With the advent of sentinel lymph node biopsy, the axilla can be accurately staged in patients with T1-T3, clinically node-negative breast cancers while avoiding the morbidity of axillary lymph node dissection if the nodes do not contain cancer. Recent clinical trials suggest that for women with metastases to 1 or 2 sentinel nodes, the radiation and systemic therapy that are part of modern multimodality breast cancer treatment can replace axillary dissection when breast-conserving therapy is undertaken. For those with greater disease burden or those undergoing mastectomy, axillary dissection remains standard management.

Re. Multimodality Breast Cancer Screening in Women with a Familial or Genetic Predisposition

Earlier this year in Current Oncology, Trop and colleagues added new information to support the claim that screening with magnetic resonance imaging (MRI) for breast cancer is superior—in terms of sensitivity— to routine mammography [...]

Multimodality Breast Cancer Screening in Women with a Familial or Genetic Predisposition

Women with a predisposition for breast cancer require a tailored screening program for early cancer detection. We evaluated the performance of mammography (MG), ultrasonography (US), and magnetic resonance imaging (MRI) screening in these women. In asymptomatic women either confirmed as BRCA1/2 carriers, or having a greater than 30% probability of being so as estimated by brcapro [Berry D, Parmigiani G. Duke SPORE (Specialized Program of Research Excellence) in Breast Cancer. 1999], we conducted a prospective comparative trial consisting of annual MRI and MG, and biannual US and clinical breast examination. All evaluations were done within 30 days of one another. For each screening round, imaging tests were independently interpreted by three radiologists. The study enrolled 184 women, and 387 screening rounds were performed, detecting 12 cancers (9 infiltrating, 3 in situ), for an overall cancer yield of 6.5%. At diagnosis, 7 infiltrating cancers were smaller than 2 cm (T1); only 1 woman presented with axillary nodal metastases. All tumours were negative for the human epidermal growth factor receptor 2. Of the 12 cancers, MRI detected 10, and MG, 7; US did not identify any additional cancers. The overall recall rate after MRI was 21.8%, as compared with 11.4% for US and 16.1% for MG. Recall rates declined with successive screening rounds. In total, 45 biopsies were performed: 21 as a result of an US abnormality; 17, because of an MRI lesion; and 7, because of a MG anomaly. In high-risk women, MRI offers the best sensitivity for breast cancer screening. The combination of yearly MRI and MG reached a negative predictive value of 100%. The recall rate is greatest with MRI, but declines for all modalities with successive screening rounds.

Evaluating the Correlation between Film Mammography and MRI for Screening Women with Increased Breast Cancer Risk

Breast magnetic resonance imaging (MRI) is increasingly being added to mammography for screening asymptomatic women at increased risk of breast cancer. Because the direction and extent of correlation between mammography and MRI could potentially result in over- or underestimation of the diagnostic gain related to using MRI as an adjunct to mammographic screening, we performed an analysis to evaluate the extent of correlation between mammography and MRI. We reviewed the published literature to identify multimodality breast cancer screening studies reporting the sensitivity of mammography and MRI, alone and in combination, for breast cancer diagnosis. After calculating the expected sensitivity of combined mammography and MRI under conditions of test independence (no correlation), we compared the calculated and observed sensitivities for combined mammography and MRI. We then calculated correlation coefficients for mammography and MRI. Seven studies of multimodality screening in women at increased risk of developing breast cancer were included for analysis. Of these studies, the correlation between film mammography and MRI was positive in three studies, negative in two studies, and not identified in two studies. The calculated correlation coefficients ranged from -0.38 to 0.18. In six of seven studies, the 95% confidence interval for the correlation coefficient included 0.0, indicating no significant correlation. Evidence from published trials of multimodality breast cancer screening identified no statistically significant correlation between film mammography and MRI. Using both tests for breast cancer screening is likely to improve the early detection of breast cancer in women at increased risk.

Cardiac Risks in Multimodal Breast Cancer Treatment

Cardiac Risks in Multimodal Breast Cancer Treatment

Model-based registration of X-ray mammograms and MR images of the female breast

We present a new approach for automatic registration of X-ray mammograms and MR images. Multimodal breast cancer diagnosis is supported by automatic localization of small lesions, which are only visible in the mammograms or in the MR image. To cope with the huge deformation of the breast during mammography, a finite element model of the deformable behavior of the breast is applied during the registration. An evaluation of the registration with six clinical data sets resulted in an accurate localization with a mean displacement of 4.3 mm (/spl plusmn/1 mm) and 3.9 mm (/spl plusmn/1.7 mm) for predicting the lesion position in mammograms and in the MR images, respectively.