Comparative Diagnostic Utility of Low-Dose Breast-Specific Gamma Imaging to Current Clinical Standard.

To retrospectively compare low-dose (7-10 mCi) to high-dose (15-30 mCi) breast-specific gamma imaging (BSGI) in the detection of breast cancer. A retrospective review of 223 consecutive women who underwent BSGI exam between February 2011 and August 2013 with subsequent pathologic analysis was performed. Women were divided into low-dose and high-dose groups. The results of BSGI and pathology were compared, and the sensitivity, positive predictive value (PPV), and negative predictive value (NPV) were determined. A subgroup analysis was performed to evaluate specificity using benign follow-up imaging to establish true-negative results. There were 223 women who met inclusion criteria with 109 patients with 153 lesions in the low-dose group and 114 patients with 145 lesions in the high-dose group. Pathologic correlation demonstrates sensitivities of 97.6% (95% CI = 90.9-99.6%) and 94.6% (95% CI = 84.2-98.6%; p = 0.093), PPVs of 62.1% (95% CI = 53.2-70.3%) and 50.5% (95% CI = 40.6-60.3%, p = 0.089), and NPVs of 90.5% (95% CI = 68.2-98.3%) and 92.5% (95% CI = 78.5-98.0%, p = 0.781) in the low-dose and high-dose groups, respectively. Subgroup analysis included 72 patients with 98 lesions in the low-dose group and 116 patients with 132 lesions in the high-dose group, with a specificity of 53.7% (95% CI = 39.7-67.1%) and 66.3% (95% CI = 56.2-75.2%%, p = 0.143), respectively. Low-dose BSGI demonstrated high sensitivity and NPV in the detection of breast cancer comparable to the current standard dose BSGI, with moderate specificity and PPV in a limited subgroup analysis, which was associated with a substantial number of false-positives.

miR-638 mediated regulation of BRCA1 affects DNA repair and sensitivity to UV and cisplatin in triple-negative breast cancer.

INTRODUCTION: Triple-negative breast cancer (TNBC) represents 15 to 20% of all types of breast cancer; however, it accounts for a large number of metastatic cases and deaths, and there is still no effective treatment. The deregulation of microRNAs (miRNAs) in breast cancer has been widely reported. We previously identified that miR-638 was one of the most deregulated miRNAs in breast cancer progression. Bioinformatics analysis revealed that miR-638 directly targets BRCA1. The aim of this study was to investigate the role of miR-638 in breast cancer prognosis and treatment. METHODS: Formalin-fixed, paraffin-embedded (FFPE) breast cancer samples were microdissected into normal epithelial and invasive ductal carcinoma (IDC) cells, and total RNA was isolated. Several breast cancer cell lines were used for the functional analysis. miR-638 target genes were identified by TARGETSCAN-VERT 6.2 and miRanda. The expression of miR-638 and its target genes was analyzed by real-time qRT-PCR and Western blotting. Dual-luciferase reporter assay was employed to confirm the specificity of miR-638 target genes. The biological function of miR-638 was analyzed by MTT chemosensitivity, matrigel invasion and host cell reactivation assays. RESULTS: The expression of miR-638 was decreased in IDC tissue samples compared to their adjacent normal controls. The decreased miR-638 expression was more prevalent in non-TNBC compared with TNBC cases. miR-638 expression was significantly downregulated in breast cancer cell lines compared to the immortalized MCF-10A epithelial cells. BRCA1 was predicted as one of the direct targets of miR-638, which was subsequently confirmed by dual-luciferase reporter assay. Forced expression of miR-638 resulted in a significantly reduced proliferation rate as well as decreased invasive ability in TNBC cells. Furthermore, miR-638 overexpression increased sensitivity to DNA-damaging agents, ultraviolet (UV) and cisplatin, but not to 5-fluorouracil (5-FU) and epirubicin exposure in TNBC cells. Host cell reactivation assays showed that miR-638 reduced DNA repair capability in post UV/cisplatin-exposed TNBC cells. The reduced proliferation, invasive ability, and DNA repair capabilities are associated with downregulated BRCA1 expression. CONCLUSIONS: Our findings suggest that miR-638 plays an important role in TNBC progression via BRCA1 deregulation. Therefore, miR-638 might serve as a potential prognostic biomarker and therapeutic target for breast cancer.

Breast-specific gamma imaging for the detection of breast cancer in dense versus nondense breasts.

OBJECTIVE: The purpose of this study was to evaluate the sensitivity of breast-specific gamma imaging (BSGI) for the detection of breast cancer in dense versus nondense breasts. MATERIALS AND METHODS: This was a retrospective study of 341 women with biopsy-proven breast cancer diagnosed from January 2004 to August 2009 who underwent BSGI before surgical excision. Patients with predominantly fatty replaced (BI-RADS density 1) or scattered fibroglandular tissue (BI-RADS density 2) breasts were classified as nondense, and those with heterogeneously dense (BI-RADS density 3) or extremely dense tissue (BIRADS density 4) were classified as dense. BSGI examinations exhibiting focal increased radiotracer uptake in the area of biopsy-proven cancer were classified as positive according to BSGI reports in the medical record. The sensitivity of BSGI was calculated using Microsoft Excel 2003. Between-group differences were evaluated statistically using the Student t test for continuous variables and the chi-square test for categoric variables, with p < 0.05 considered statistically significant. RESULTS: The overall sensitivity of BSGI for breast cancer detection was 95.4%. Positive BSGI examinations were present in 136 of 142 nondense breast cancers and 195 of 205 dense breast cancers, for sensitivities of 95.8% and 95.1%, respectively. There was no significant difference in BSGI breast cancer detection and parenchymal breast density (p = 0.459). CONCLUSION: BSGI has high sensitivities for the detection of breast cancer in women with dense and nondense breasts and is an effective adjunct imaging modality in women with both dense and nondense breasts.

Breast-specific gamma imaging influences surgical management in patients with breast cancer.

Breast-specific gamma imaging (BSGI) is a physiologic breast imaging modality that provides more sensitive detection of breast lesions than mammography or ultrasound, and appears to have greater specificity than breast MRI. The purpose of this study was to evaluate how often BSGI changed surgical management in patients with breast cancer. Charts were reviewed from 218 consecutive eligible patients who had preoperative evaluation with BSGI or MRI before surgery for breast cancer from January 2008 to May 2010. Patients who were initially considered eligible for breast-conserving therapy (BCT) were evaluated to determine how many ultimately had mastectomies. Patients who underwent mastectomy because of personal choice or ineligibility for BCT were excluded. Management was changed to mastectomy in 11.9% of those who had BSGI and 28.9% of those who had MRI. Review of pathology demonstrated that all patients who underwent mastectomies were not candidates for breast conservation. 15.4% of patients who underwent BCT based on BSGI findings required a single re-excision due to positive surgical margins. 14.4% required mastectomy. In the MRI group, 18.8% required a single re-excision, and 6.3% required mastectomy. Evaluation with BSGI changed management to mastectomy in a substantial proportion of patients believed to be eligible for BCT following standard imaging. BSGI is effective in evaluation of extent of disease in patients with breast cancer, and is comparable to MRI in terms of its influence on surgical management.

Mastectomy and contralateral prophylactic mastectomy rates: an institutional review.

BACKGROUND: Breast conservation surgery (BCS) followed by radiation is as effective as mastectomy for long-term survival and is considered standard of care for early-stage breast cancer. An increasing number of patients are opting for cancer-side mastectomies (CM) and often contralateral prophylactic mastectomies (CPM). Our study investigates if there are increasing trends in our patient population toward CM and CPM and identifies common factors associated with those electing to have more extensive surgery. METHODS: A retrospective analysis was performed on 812 breast cancer surgeries between January 2001 and December 2009 at The George Washington University Breast Care Center. BCS-eligible patients who elected to have BCS were compared with those who chose CM. Patients who underwent CM were compared with patients undergoing CM and CPM. RESULTS: A personal or family history of breast cancer and larger tumor size were positively associated with choosing CM in BCS-eligible patients. A nonstatistically significant trend toward CM was seen in younger patients. Age, family history, fewer children, Caucasian race, and reconstructive surgery were positively associated with choosing CPM. CONCLUSION: Mastectomy rates at this institution have not shown the recent sharp increase observed by some authors. The association of age, race, family history, and parity with CPM has been corroborated in multiple studies. However, there is disagreement between statistically significant findings among investigators evaluating factors associated with CPM, and there is limited data in the literature characterizing BCS-eligible patients who chose CM. Larger prospective studies are necessary to further evaluate CM and CPM rates.

Factors associated with re-excision in patients with early-stage breast cancer treated with breast conservation therapy.

One of the risks of breast conservation surgery is local recurrence, which predominantly occurs as a result of inadequate surgical margins. The purpose of this study was to identify factors associated with close or positive surgical margins leading to reexcision (RE). The charts of 532 consecutive breast cancer patients treated at our center between September 2001 and June 2007 were reviewed to evaluate patients who opted for breast conservation surgery and needed reexcision. A total of 351 patients were treated with breast conservation, of which 118 (34%) had positive or close surgical margins and went on to RE. On univariate analysis, factors that significantly correlated with RE (P < 0.05) were preoperative diagnosis, final pathology, size of tumor, and presentation with nipple discharge. RE was necessary in 53 per cent of patients with a preoperative diagnosis of ductal carcinoma in situ (DCIS), 57 per cent of patients diagnosed by surgical excision, 86 per cent of patients presenting with nipple discharge, and 87 per cent of patients with DCIS or invasive carcinoma with extensive intraductal component in the final pathology. Additionally, 53 per cent of patients with T3 tumors required RE. Age, race, and grade of tumor had no effect on RE rates. Most (75%) patients were able to ultimately have breast conservation.

miR-671-5p inhibits epithelial-to-mesenchymal transition by downregulating FOXM1 expression in breast cancer.

MicroRNA (miRNA) dysfunction is associated with a variety of human diseases, including cancer. Our previous study showed that miR-671-5p was deregulated throughout breast cancer progression. Here, we report for the first time that miR-671-5p is a tumor-suppressor miRNA in breast tumorigenesis. We found that expression of miR-671-5p was decreased significantly in invasive ductal carcinoma (IDC) compared to normal in microdissected formalin-fixed, paraffin-embedded (FFPE) tissues. Forkhead Box M1 (FOXM1), an oncogenic transcription factor, was predicted as one of the direct targets of miR-671-5p, which was subsequently confirmed by luciferase assays. Forced expression of miR-671-5p in breast cancer cell lines downregulated FOXM1 expression, and attenuated the proliferation and invasion in breast cancer cell lines. Notably, overexpression of miR-671-5p resulted in a shift from epithelial-to-mesenchymal transition (EMT) to mesenchymal-to-epithelial transition (MET) phenotypes in MDA-MB-231 breast cancer cells and induced S-phase arrest. Moreover, miR-671-5p sensitized breast cancer cells to cisplatin, 5-fluorouracil (5-FU) and epirubicin exposure. Host cell reactivation (HCR) assays showed that miR-671-5p reduces DNA repair capability in post-drug exposed breast cancer cells. cDNA microarray data revealed that differentially expressed genes when miR-671-5p was transfected are associated with cell proliferation, invasion, cell cycle, and EMT. These data indicate that miR-671-5p functions as a tumor suppressor miRNA in breast cancer by directly targeting FOXM1. Hence, miR-671-5p may serve as a novel therapeutic target for breast cancer management.

Correlation of lymphoscintigraphy with the number of sentinel lymph nodes identified intraoperatively in patients with breast cancer.

BACKGROUND: Numerous studies have evaluated the benefit of performing lymphoscintigraphy for the sentinel lymph node procedure in breast cancer patients. The purpose of this study is to determine if lymphoscintigraphy accurately predicts the number of radioactive sentinel lymph nodes (SLNs) identified during surgery for breast cancer patients. METHODS: From October 2001 to June 2004, SLN biopsy was attempted in 112 patients with breast cancer using a combination of blue dye and radioisotope. Lymphoscintigraphy was performed in 98 of the patients. A lymph node was considered an SLN when it was stained with blue dye, had a blue lymphatic afferent, had increased radioactivity, or was abnormal by palpation. RESULTS: Lymphoscintigraphy accurately predicted the number of radioactive SLN identified intraoperatively in 47 patients. In 44 of the patients who did not have concordance, there were more SLN identified intraoperatively than were seen on lymphoscintigraphy. In the other 8 patients, there were fewer SLN identified intraoperatively than seen on lymphoscintigraphy. CONCLUSIONS: Lymphoscintigraphy accurately predicted the number of SLN identified intraoperatively in only 47% of the patients in this study. In a majority of the patients in whom the lymphoscintigraphy was not concordant, the number of SLN identified intraoperatively was underestimated. Thus, although lymphoscintigraphy is beneficial in showing that at least 1 radioactive SLN will be identified intraoperatively, it does not accurately predict the number.

Role of deregulated microRNAs in breast cancer progression using FFPE tissue.

MicroRNAs (miRNAs) contribute to cancer initiation and progression by silencing the expression of their target genes, causing either mRNA molecule degradation or translational inhibition. Intraductal epithelial proliferations of the breast are histologically and clinically classified into normal, atypical ductal hyperplasia (ADH), ductal carcinoma in situ (DCIS) and invasive ductal carcinoma (IDC). To better understand the progression of ductal breast cancer development, we attempt to identify deregulated miRNAs in this process using Formalin-Fixed, Paraffin-Embedded (FFPE) tissues from breast cancer patients. Following tissue microdissection, we obtained 8 normal, 4 ADH, 6 DCIS and 7 IDC samples, which were subject to RNA isolation and miRNA expression profiling analysis. We found that miR-21, miR-200b/c, miR-141, and miR-183 were consistently up-regulated in ADH, DCIS and IDC compared to normal, while miR-557 was uniquely down-regulated in DCIS. Interestingly, the most significant miRNA deregulations occurred during the transition from normal to ADH. However, the data did not reveal a step-wise miRNA alteration among discrete steps along tumor progression, which is in accordance with previous reports of mRNA profiling of different stages of breast cancer. Furthermore, the expression of MSH2 and SMAD7, two important molecules involving TGF-ß pathway, was restored following miR-21 knockdown in both MCF-7 and Hs578T breast cancer cells. In this study, we have not only identified a number of potential candidate miRNAs for breast cancer, but also found that deregulation of miRNA expression during breast tumorigenesis might be an early event since it occurred significantly during normal to ADH transition. Consequently, we have demonstrated the feasibility of miRNA expression profiling analysis using archived FFPE tissues, typically with rich clinical information, as a means of miRNA biomarker discovery.

Breast-specific gamma imaging in the detection of atypical ductal hyperplasia and lobular neoplasia.

RATIONALE AND OBJECTIVES: Atypical lesions such as atypical ductal hyperplasia (ADH) and lobular neoplasia are nonmalignant lesions that are associated with significant increased risk of developing breast cancer. Atypical lesions have been reported to present with focal increased radiotracer uptake on breast-specific gamma imaging (BSGI) examination, a novel physiologic tool for the detection of breast cancer. To date the sensitivity of BSGI in the detection of atypical lesions has not been reported. The purpose of this study is to determine the sensitivity of BSGI in detecting ADH and lobular neoplasia. MATERIALS AND METHODS: A total of 1316 patients who received a BSGI exam between January 2006 and July 2009 were retrospectively reviewed. All patients who underwent minimally invasive biopsy and subsequent surgical excision where the highest pathology was solely ADH or lobular neoplasia (reported as ALH, lobular carcinoma in situ or lobular neoplasia), according to the pathology database were included (n = 15). The sensitivity was determined as the percentage of positive BSGI exams out of all patients diagnosed with ADH or lobular neoplasia who received a BSGI. RESULTS: Patient ages ranged from 39 to 67 (mean, 52). Eight of 15 patients had ADH, 6/15 lobular neoplasia, and 1/15 ADH and lobular neoplasia in one lesion. Fifteen of the 15 (100%) patients with surgically confirmed ADH or lobular neoplasia had a positive BSGI, with focally increased radiotracer uptake at the site of the verified high-risk lesion. CONCLUSION: BSGI has a high sensitivity for the detection of atypical, high-risk breast lesions. A diagnosis of an atypical lesion is concordant with focal increased radiotracer uptake with BSGI and can identify women at increased risk for breast cancer.

Mastectomy and contralateral prophylactic mastectomy rates: an institutional review.

Background. Breast conservation surgery (BCS) followed by radiation is as effective as mastectomy for long-term survival and is considered standard of care for early-stage breast cancer. An increasing number of patients are opting for cancer-side mastectomies (CM) and often contralateral prophylactic mastectomies (CPM). Our study investigates if there are increasing trends in our patient population toward CM and CPM and identifies common factors associated with those electing to have more extensive surgery.Methods. A retrospective analysis was performed on 812 breast cancer surgeries between January 2001 and December 2009 at The George Washington University Breast Care Center. BCS-eligible patients who elected to have BCS were compared with those who chose CM. Patients who underwent CM were compared with patients undergoing CM and CPM.Results. A personal or family history of breast cancer and larger tumor size were positively associated with choosing CM in BCS-eligible patients. A nonstatistically significant trend toward CM was seen in younger patients. Age, family history, fewer children, Caucasian race, and reconstructive surgery were positively associated with choosing CPM.Conclusion. Mastectomy rates at this institution have not shown the recent sharp increase observed by some authors. The association of age, race, family history, and parity with CPM has been corroborated in multiple studies. However, there is disagreement between statistically significant findings among investigators evaluating factors associated with CPM, and there is limited data in the literature characterizing BCS-eligible patients who chose CM. Larger prospective studies are necessary to further evaluate CM and CPM rates.

Detection of occult foci of breast cancer using breast-specific gamma imaging in women with one mammographic or clinically suspicious breast lesion.

RATIONALE AND OBJECTIVES: The aim of this study was to determine how often breast-specific gamma imaging (BSGI) identifies occult cancerous lesions in women with one suspicious lesion detected on mammography or physical exam. MATERIALS AND METHODS: A retrospective review was performed of the records of all patients who underwent BSGI between January 1, 2004, and June 4, 2007. Included in the study were 159 women who had one suspicious breast lesion on physical exam and/or mammography and who underwent BSGI to evaluate for occult lesions in the breast. All patients had one or more foci of cancer proven pathologically. BSGI findings were classified as normal or abnormal on the basis of the presence of focal radiotracer uptake. RESULTS: BSGI detected additional suspicious lesions occult to mammography and physical exam in 46 of 159 women (29%). BSGI identified occult cancer in 14 of 40 women (35%) who underwent biopsy or excision because of BSGI findings and in 14 of the 159 (9%) women in this study. In nine women, the occult cancer was present in the same breast as the index lesion (6%), and in five women, the occult cancer was found in the contralateral breast (3%). CONCLUSIONS: BSGI is an effective imaging modality in the identification of mammographically and clinically occult cancer in women with one suspicious breast lesion.

Nonvisualization of a sentinel lymph node on lymphoscintigraphy requiring reinjection of sulfur colloid in a patient with breast cancer.

PURPOSE: The injection techniques and use of lymphoscintigraphy for sentinel lymph node (SLN) biopsy in breast cancer patients vary. Some do not advocate routine use of lymphoscintigraphy. The purpose of this case report is to illustrate when lymphoscintigraphy should be used. METHODS: At our institution, we use periareolar intradermal injections of 0.6 mCi Tc-99m sulfur colloid followed by lymphoscintigraphy with reported identification rates greater than 99%. The only patient in our series who did not have a SLN identified had presented after excisional biopsy of an upper outer quadrant cancer. We report the case of another patient who presented after excision of an upper outer quadrant invasive ductal carcinoma and had no evidence of lymphatic drainage on lymphoscintigraphy after the periareolar injections of radioisotope. RESULTS: Additional injections of 0.4 mCi Tc-99m sulfur colloid were performed lateral to the incision in the upper outer quadrant. On lymphoscintigraphy a SLN was visualized and was subsequently successfully identified intraoperatively. CONCLUSION: This case report supports the value of lymphoscintigraphy for successful identification of a SLN in a patient with prior surgery. We therefore recommend imaging patients who have had prior breast surgery, particularly excisions in the upper outer quadrant.

Evaluation of intraoperative scrape cytology for sentinel lymph node biopsy in patients with breast cancer.

The techniques for intraoperative evaluation of sentinel lymph nodes (SLNs) vary. The most common methods include frozen section, imprint cytology/touch preparation cytology, and scrape cytology (SC). The purpose of this study was to evaluate whether there is concordance between the intraoperative SC and the final pathology of SLNs in patients with breast cancer. From October 2001 to June 2005, sentinel lymph node biopsies were attempted in 181 patients with breast cancer using a combination of blue dye and radioisotope. A lymph node was considered an SLN when it was stained with blue dye, had a blue lymphatic afferent, had increased radioactivity, or was abnormal by palpation. SLNs were successfully identified in 180 patients, for an identification rate of 99.4%. Forty-five patients had positive SLNs. In 16 (35%) of those patients, the SLNs were negative intraoperatively by SC. All of the false negatives occurred in SLNs with micrometastases. Thus, SC is an excellent method for identifying macrometastases intraoperatively, but less successful for micrometastases.

Evaluation of the benefit of using blue dye in addition to radioisotope for sentinel lymph node biopsy in patients with breast cancer.

The techniques for performing sentinel lymph node biopsy (SLNB) vary from institution to institution. Some advocate blue dye only, others radioisotope only, and many utilize a combination of both. The purpose of this study is to evaluate the additional benefit that blue dye provides when used in combination with a radioisotope. From October 2001 to June 2004, 102 SLNBs were attempted in 99 patients with breast cancer using a combination of blue dye and radioisotope. A lymph node was considered a sentinel lymph node (SLN) when it was stained with blue dye, had a blue lymphatic afferent, or had increased radioactivity. Ninety-eight patients had 101 successful identifications of SLNs, for an identification rate of 99%. Twenty-eight patients had positive SLNs. In three of those patients, although there were SLNs identified by both techniques, the positive SLNs were identified with only blue dye. Of the 102 SLNB procedures, there were two patients whose only SLN was identified by blue dye only. Although blue dye did not improve the identification rate, there was a definite benefit in improving the false-negative rate.

Occult breast cancer: scintimammography with high-resolution breast-specific gamma camera in women at high risk for breast cancer.

PURPOSE: To prospectively evaluate a high-resolution breast-specific gamma camera for depicting occult breast cancer in women at high risk for breast cancer but with normal mammographic and physical examination findings. MATERIALS AND METHODS: Institutional Review Board approval and informed consent were obtained. The study was HIPAA compliant. Ninety-four high-risk women (age range, 36-78 years; mean, 55 years) with normal mammographic (Breast Imaging Reporting and Data System [BI-RADS] 1 or 2) and physical examination findings were evaluated with scintimammography. After injection with 25-30 mCi (925-1110 MBq) of technetium 99m sestamibi, patients were imaged with a high-resolution small-field-of-view breast-specific gamma camera in craniocaudal and mediolateral oblique projections. Scintimammograms were prospectively classified according to focal radiotracer uptake as normal (score of 1), with no focal or diffuse uptake; benign (score of 2), with minimal patchy uptake; probably benign (score of 3), with scattered patchy uptake; probably abnormal (score of 4), with mild focal radiotracer uptake; and abnormal (score of 5), with marked focal radiotracer uptake. Mammographic breast density was categorized according to BI-RADS criteria. Patients with normal scintimammograms (scores of 1, 2, or 3) were followed up for 1 year with an annual mammogram, physical examination, and repeat scintimammography. Patients with abnormal scintimammograms (scores of 4 or 5) underwent ultrasonography (US), and those with focal hypoechoic lesions underwent biopsy. If no lesion was found during US, patients were followed up with scintimammography. Specific pathologic findings were compared with scintimammographic findings. RESULTS: Of 94 women, 78 (83%) had normal scintimammograms (score of 1, 2, or 3) at initial examination and 16 (17%) had abnormal scintimammograms (score of 4 or 5). Fourteen (88%) of the 16 patients had either benign findings at biopsy or no focal abnormality at US; in two (12%) patients, invasive carcinoma was diagnosed at US-guided biopsy (9 mm each at pathologic examination). CONCLUSION: High-resolution breast-specific scintimammography can depict small (<1-cm), mammographically occult, nonpalpable lesions in women at increased risk for breast cancer not otherwise identified at mammography or physical examination.