The relationship of single-strand breaks in DNA to breast cancer risk and to tissue concentrations of oestrogens.

CONTEXT: Clinical study of breast cancer patients in Chicago, IL, USA. OBJECTIVE: Ascertain the utility of measurements of single-strand breaks (SSB) in DNA for assessment of breast cancer risk. METHODS: Fine-needle aspirates of the breast, SSB by nick translation, percent breast density (PBD), Gail model risk, cumulative methylation index (CMI), enzymes of DNA repair and tissue antioxidants. RESULTS: DNA repair enzymes and 4-hydroxyestradiol were negatively associated with SSB; CMI and PBD were positively associated. CONCLUSIONS: Quantitative measurement of SSBs by this procedure indicates the relative number of SSBs and is related to promoter methylation, antioxidant availability and percent breast density.

Diagnostic accuracy of sentinel node identification is maintained with the addition of local lidocaine and subareolar radioactive colloid injection.

Preoperative sentinel node localization (SNL) using a subareolar injection of radiotracer technetium-99m-sulfur colloid (Tc(99m)SC) is associated with significant pain. Lidocaine use during SNL is not widely adopted partly due to a concern that it can obscure sentinel node identification and reduce its diagnostic accuracy. We prospectively identified women with a biopsy-proven infiltrating breast cancer who were awaiting a SNL. The women completed the McGill pain questionnaire, Visual Analog Scale, and Wong-Baker FACES Pain Rating Scale prior to and following SNL. We identified a retrospective cohort of women with similar demographic and tumor characteristics who did not receive lidocaine before SNL. We compared sentinel lymph node identification rates in the two cohorts. We used Wilcoxon rank sum tests to compare continuous measures and Fisher's exact test for categorical measures. Between January 2011 to July 2012, 110 women consented, and 105 were eligible for and received lidocaine prior to Tc(99m)SC injection. The post-lidocaine identification rate of SNL was 95 % with Tc(99m)SC, and 100 % with the addition of intraoperative methylene blue dye/saline. Pain range prior to and following the SNL was unchanged (P = 0.703). We identified 187 women from 2005 to 2009 who did not receive lidocaine during preoperative SNL. There was no significant difference in the success rate of SNL, with or without lidocaine (P = 0.194). The administration of lidocaine during SNL prevents pain related to isotope injection while maintaining the success rate. We have changed our practice at our center to incorporate the use of lidocaine during all SNL.

A short-term biomarker modulation study of simvastatin in women at increased risk of a new breast cancer.

Observational studies have demonstrated a decreased incidence of cancers among users of HMG CoA reductase inhibitors (statins) and a reduced risk of recurrence among statin users diagnosed with early stage breast cancer. We initiated a prospective study to identify potential biomarkers of simvastatin chemopreventive activity that can be validated in future trials. The contralateral breast of women with a previous history of breast cancer was used as a high-risk model. Eligible women who had completed all planned treatment of a prior stage 0-III breast cancer received simvastatin 40 mg orally daily for 24-28 weeks. At baseline and end-of-study, we measured circulating concentrations of high-sensitivity C-reactive protein (hsCRP), estrogens, and fasting lipids; breast density on contralateral breast mammogram; and quality of life by Rand Short Form 36-Item health survey. Fifty women were enrolled with a median age of 53 years. Total cholesterol, LDL cholesterol, triglyceride, and hsCRP fell significantly during the study (P values < 0.001, <0.001, 0.003, and 0.05, respectively). Estrone sulfate concentrations decreased with simvastatin treatment (P = 0.01 overall), particularly among post-menopausal participants (P = 0.006). We did not observe a significant change in circulating estradiol or estrone concentrations, contralateral mammographic breast density, or reported physical functioning or pain scores. This study demonstrates the feasibility of short-term biomarker modulation studies using the contralateral breast of high-risk women. Simvastatin appears to modulate estrone sulfate concentrations and its potential chemopreventive activity in breast cancer warrants further investigation.

The role of ultrasound-guided fine-needle aspiration of axillary nodes in the staging of breast cancer.

BACKGROUND: As a complement to sentinel node dissection (SLND), we evaluated ultrasound-guided fine-needle aspiration (USFNA) of normal and abnormal axillary nodes in breast cancer patients. We hypothesized that USFNA would be accurate for primary breast tumors larger than 2 cm. METHODS: We retrospectively reviewed 68 patients who underwent 69 preoperative USFNAs from 2003 to 2005. The results of 65 preoperative USFNA were compared with the results of SLND or axillary node dissection (ALND) for concordance. Four USFNAs were excluded from analysis because of a complete response to neoadjuvant therapy. We evaluated whether primary tumor features (histology, size, grade, vascular invasion, estrogen/progesterone receptor status and Her-2-neu status) predicted concordance of USFNA results and the final lymph node pathology. RESULTS: Of 65 axillae analyzed, 39 (60%) were positive, four (6%) were non-diagnostic, and 22 (34%) were negative by USFNA. USFNA had 89% sensitivity, 100% specificity, and 100% positive predictive value (PPV) in patients with palpable or ultrasonographically suspicious nodes. USFNA sensitivity dropped significantly for nonpalpable, ultrasonographically normal nodes (54%), while specificity and PPV remained 100%. None of the primary tumor features predicted concordance of USFNA and SLND/ALND. CONCLUSIONS: USFNA of axillary nodes has a high specificity and PPV in clinically or radiologically suspicious nodes. Sensitivity of USFNA is low for nodes of normal appearance, but positive USFNA may allow definitive management of the axilla without a SLND. Thus, USFNA of normal appearing nodes might be beneficial in cases where decisions regarding neoadjuvant chemotherapy would be affected by the results.

The role of breast MRI in the management of patients with breast disease.

Breast MRI has paved the way for new thinking regarding the workup of women recently diagnosed with breast cancer and the screening of high-risk women. The routine use of MRI preoperatively is advocated, particularly in young patients and women with dense breasts where mammography is significantly less sensitive for the detection of malignancy. Additionally, MRI is particularly helpful in those women who have core biopsy results showing extensive intraductal component (>25%) orinvasive lobular carcinoma, and in those women with increased risk of positive margins. However, as with any imaging modality, breast magnetic resonance has limitations. Because breast magnetic resonance has lower specificity than some modalities, clinicians must be selective in identifying those women most likely to benefit from this additional imaging. Many recent publications show that MRI does not unduly raise the false-positive biopsy rate while providing specificity similar to that of mammography and higher than that of ultrasound. Positive margin rates for breast conservation therapy range from 30% to 50% and the achievement of negative margins is directly related to low recurrence rates. Magnetic resonance provides improved preoperative staging, which in turn may reduce recurrence rates and improve patient outcome. Breast MRI should be used in concert with other modalities, such as mammography and ultrasound, for the highest sensitivity for detecting malignancy. Long-term studies are needed to validate the impact of screening and diagnostic breast MRI on patient outcomes.

Gene Methylation and Cytological Atypia in Random Fine-Needle Aspirates for Assessment of Breast Cancer Risk.

Methods to determine individualized breast cancer risk lack sufficient sensitivity to select women most likely to benefit from preventive strategies. Alterations in DNA methylation occur early in breast cancer. We hypothesized that cancer-specific methylation markers could enhance breast cancer risk assessment. We evaluated 380 women without a history of breast cancer. We determined their menopausal status or menstrual cycle phase, risk of developing breast cancer (Gail model), and breast density and obtained random fine-needle aspiration (rFNA) samples for assessment of cytopathology and cumulative methylation index (CMI). Eight methylated gene markers were identified through whole-genome methylation analysis and included novel and previously established breast cancer detection genes. We performed correlative and multivariate linear regression analyses to evaluate DNA methylation of a gene panel as a function of clinical factors associated with breast cancer risk. CMI and individual gene methylation were independent of age, menopausal status or menstrual phase, lifetime Gail risk score, and breast density. CMI and individual gene methylation for the eight genes increased significantly (P < 0.001) with increasing cytological atypia. The findings were verified with multivariate analyses correcting for age, log (Gail), log (percent density), rFNA cell number, and body mass index. Our results demonstrate a significant association between cytological atypia and high CMI, which does not vary with menstrual phase or menopause and is independent of Gail risk and mammographic density. Thus, CMI is an excellent candidate breast cancer risk biomarker, warranting larger prospective studies to establish its utility for cancer risk assessment. Cancer Prev Res; 9(8); 673-82. ©2016 AACR.

Breast Cancer Screening.

Breast cancer screening has become a controversial topic. Understanding the points of contention requires an appreciation of the conceptual framework underpinning cancer screening in general, knowledge of the strengths and limitations of available screening modalities, and familiarity with published clinical trial data. This review is data intense with the intention of presenting enough information to permit the reader to enter into the discussion with an ample knowledge base. The focus throughout is striking a balance between the benefits and harms of breast cancer screening.

TBCRC 008: early change in 18F-FDG uptake on PET predicts response to preoperative systemic therapy in human epidermal growth factor receptor 2-negative primary operable breast cancer.

UNLABELLED: Epigenetic modifiers, including the histone deacetylase inhibitor vorinostat, may sensitize tumors to chemotherapy and enhance outcomes. We conducted a multicenter randomized phase II neoadjuvant trial of carboplatin and nanoparticle albumin-bound paclitaxel (CP) with vorinostat or placebo in women with stage II/III, human epidermal growth factor receptor 2 (HER2)-negative breast cancer, in which we also examined whether change in maximum standardized uptake values corrected for lean body mass (SUL(max)) on (18)F-FDG PET predicted pathologic complete response (pCR) in breast and axillary lymph nodes. METHODS: Participants were randomly assigned to 12 wk of preoperative carboplatin (area under the curve of 2, weekly) and nab-paclitaxel (100 mg/m(2) weekly) with vorinostat (400 mg orally daily, days 1-3 of every 7-d period) or placebo. All patients underwent (18)F-FDG PET and research biopsy at baseline and on cycle 1 day 15. The primary endpoint was the pCR rate. Secondary objectives included correlation of change in tumor SUL(max) on (18)F-FDG PET by cycle 1 day 15 with pCR and correlation of baseline and change in Ki-67 with pCR. RESULTS: In an intent-to-treat analysis (n = 62), overall pCR was 27.4% (vorinostat, 25.8%; placebo, 29.0%). In a pooled analysis (n = 59), we observed a significant difference in median change in SUL(max) 15 d after initiating preoperative therapy between those achieving pCR versus not (percentage reduction, 63.0% vs. 32.9%; P = 0.003). Patients with 50% or greater reduction in SUL(max) were more likely to achieve pCR, which remained statistically significant in multivariable analysis including estrogen receptor status (odds ratio, 5.1; 95% confidence interval, 1.3-22.7; P = 0.023). Differences in baseline and change in Ki-67 were not significantly different between those achieving pCR versus not. CONCLUSION: Preoperative CP with vorinostat or placebo is associated with similar pCR rates. Early change in SUL(max) on (18)F-FDG PET 15 d after the initiation of preoperative therapy has potential in predicting pCR in patients with HER2-negative breast cancer. Future studies will further test (18)F-FDG PET as a potential treatment-selection biomarker.

Multiparametric and multinuclear magnetic resonance imaging of human breast cancer: current applications.

The exploration of novel imaging methods that have the potential to improve specificity for the identification of malignancy is still critically needed in breast imaging. Changes in physiologic alterations of soft tissue water associated with breast cancer can be visualized by magnetic resonance (MR) imaging. However, it is unlikely that a single MR parameter can characterize the complexity of breast tissue. Techniques such as multiparametric MR imaging, proton magnetic resonance spectroscopic (MRSI) imaging, and 23Na sodium MR imaging when used in combination provide a comprehensive data set with potentially more power to diagnose breast disease than any single measure alone. A combination of MR, MRSI, and 23Na sodium MR parameters may be examined in a single MR imaging examination, potentially resulting in improved specificity for radiologic evaluation of malignancy.

Borderline atypical ductal hyperplasia/low-grade ductal carcinoma in situ on breast needle core biopsy should be managed conservatively.

The differential diagnosis of low-nuclear grade intraductal epithelial proliferations of the breast includes atypical ductal hyperplasia (ADH) and ductal carcinoma in situ (DCIS). This distinction can be difficult on core needle biopsy (CNB) but can have significant clinical ramifications. We examined the clinical course of patients diagnosed on CNB with borderline ADH/DCIS lesions [marked ADH (MADH)] at our institution. A total of 74 patients were diagnosed with MADH on CNB and underwent an excisional biopsy (EB). The majority of these CNBs reviewed at outside hospitals had been classified as DCIS. Twenty patients (27%) had benign findings or lobular neoplasia in their EB, 18 (24%) had ADH, 33 (45%) had DCIS, and 3 (4%) had DCIS and invasive ductal carcinoma (IDC). Among the 38 patients who were not diagnosed with DCIS or IDC on EB, no patient underwent further surgery or radiation postoperatively. Thirty-seven of these 38 patients had no recurrences, whereas 1 patient developed a "recurrence" that on our review was likely residual localized MADH. The mean follow-up for these patients was 54 months. Of the 36 patients diagnosed with DCIS or IDC on EB, <20% required mastectomy. On review, MADH involving an intermediate-sized duct on CNB and the amount of residual lesion on imaging was significantly associated with DCIS or IDC on EB. Conversely, MADH involving columnar cell lesions and the presence of calcification on CNB were significantly associated with benign pathology on EB. In conclusion, our study provides preliminary data that justify a conservative approach to borderline ADH/DCIS lesions on CNB: that is, diagnose as MADH and treat by conservative excision.

White Paper Report of the 2010 RAD-AID Conference on International Radiology for Developing Countries: identifying sustainable strategies for imaging services in the developing world.

The 2010 RAD-AID Conference on International Radiology for Developing Countries was a multidisciplinary meeting to discuss data, experiences, and models pertaining to radiology in the developing world, where widespread shortages of imaging services reduce health care quality. The theme of this year's conference was sustainability, with a focus on establishing and maintaining imaging services in resource-limited regions. Conference presenters and participants identified 4 important components of sustainability: (1) sustainable financing models for radiology development, (2) integration of radiology and public health, (3) sustainable clinical models and technology solutions for resource-limited regions, and (4) education and training of both developing and developed world health care personnel.

Preclinical and clinical evaluation of intraductally administered agents in early breast cancer.

Most breast cancers originate in the epithelial cells lining the breast ducts. Intraductal administration of cancer therapeutics would lead to high drug exposure to ductal cells and eliminate preinvasive neoplasms while limiting systemic exposure. We performed preclinical studies in N-methyl-N'-nitrosourea-treated rats to compare the effects of 5-fluorouracil, carboplatin, nanoparticle albumin-bound paclitaxel, and methotrexate to the previously reported efficacy of pegylated liposomal doxorubicin (PLD) on treatment of early and established mammary tumors. Protection from tumor growth was observed with all five agents, with extensive epithelial destruction present only in PLD-treated rats. Concurrently, we initiated a clinical trial to establish the feasibility, safety, and maximum tolerated dose of intraductal PLD. In each eligible woman awaiting mastectomy, we visualized one ductal system and administered dextrose or PLD using a dose-escalation schema (2 to 10 mg). Intraductal administration was successful in 15 of 17 women with no serious adverse events. Our preclinical studies suggest that several agents are candidates for intraductal therapy. Our clinical trial supports the feasibility of intraductal administration of agents in the outpatient setting. If successful, administration of agents directly into the ductal system may allow for "breast-sparing mastectomy" in select women.

Changes in breast density and circulating estrogens in postmenopausal women receiving adjuvant anastrozole.

Factors associated with an increased risk of breast cancer include prior breast cancer, high circulating estrogens, and increased breast density. Adjuvant aromatase inhibitors are associated with a reduction in incidence of contralateral breast cancer. We conducted a prospective, single-arm, single-institution study to determine whether use of anastrozole is associated with changes in contralateral breast density and circulating estrogens. Eligible patients included postmenopausal women with hormone receptor-positive early-stage breast cancer who had completed local therapy, had an intact contralateral breast, and were recommended an aromatase inhibitor as their only systemic therapy. Participants received anastrozole 1 mg daily for 12 months on study. We assessed contralateral breast density and serum estrogens at baseline, 6, and 12 months. The primary endpoint was change in contralateral percent breast density from baseline to 12 months. Secondary endpoints included change in serum estrone sulfate from baseline to 12 months. Fifty-four patients were accrued. At 12 months, compared with baseline, there was a nonstatistically significant reduction in breast density (mean change: -16%, 95% CI: -30 to 2, P = 0.08) and a significant reduction in estrone sulfate (mean change: -93%, 95% CI: -94 to -91, P < 0.001). Eighteen women achieved 20% or greater relative reduction in contralateral percent density at 12 months compared with baseline; however, no measured patient or disease characteristics distinguished these women from the overall population. Large trials are required to provide additional data on the relationship between aromatase inhibitors and breast density and, more importantly, whether observed changes in breast density correlate with meaningful disease-specific outcomes.

Incidental minimal atypical lobular hyperplasia on core needle biopsy: correlation with findings on follow-up excision.

INTRODUCTION: Atypical lobular hyperplasia (ALH), often an incidental finding in breast core biopsies, is largely considered to be a risk factor for carcinoma rather than a direct precursor. However, management of ALH is controversial. We review our experience with incidental minimal ALH on core biopsy, and correlate with excision and follow-up results. DESIGN: We evaluated all cases of ALH on core biopsy from 1999 to 2009 from our institution, focusing on cases with < or =3 foci of ALH (minimal), paired excision, and no other lesion on the core biopsy that by itself would require excision. Cases with discordant clinical/radiologic impressions, suggesting that a suspicious lesion had been missed on biopsy, were excluded. Therefore, the excisions were performed because of the diagnosis of ALH. RESULTS: Of 56 cases with ALH on biopsy and paired excision, 42 showed minimal ALH. On excision, 26 had residual ALH and 13 were benign. Three cases had other atypical lesions: lobular carcinoma in situ (2 cases) and mild atypical ductal hyperplasia separate from the biopsy site (1 case). On follow-up, only 1 patient developed subsequent ALH in the same breast. No other ipsilateral lesions were later diagnosed (mean follow-up 3.2 y). CONCLUSIONS: No case with ALH on biopsy had a lesion on excision requiring further treatment, suggesting that these patients can be managed more conservatively. Furthermore, no patients were diagnosed with a higher grade lesion in the same breast on follow-up. We propose that, if there is close radiologic correlation and follow-up, minimal incidental ALH on core biopsy (< or =3 foci) does not require excision.

Multiparametric magnetic resonance imaging, spectroscopy and multinuclear (²³Na) imaging monitoring of preoperative chemotherapy for locally advanced breast cancer.

RATIONALE AND OBJECTIVES: The aim of this prospective study was to investigate using multiparametric and multinuclear magnetic resonance imaging during preoperative systemic therapy for locally advanced breast cancer. MATERIALS AND METHODS: Women with operable stage 2 or 3 breast cancer who received preoperative systemic therapy were studied using dynamic contrast-enhanced magnetic resonance imaging, magnetic resonance spectroscopy, and ²³Na magnetic resonance. Quantitative metrics of choline peak signal-to-noise ratio, total tissue sodium concentration, tumor volumes, and Response Evaluation Criteria in Solid Tumors were determined and compared to final pathologic results using receiver-operating characteristic analysis. Hormonal markers were investigated. Statistical significance was set at P < .05. RESULTS: Eighteen eligible women were studied. Fifteen responded to therapy, four (22%) with pathologic complete response and 11 (61%) with pathologic partial response. Three patients (17%) had no response. Among estrogen receptor-positive, HER2-positive, and triple-negative phenotypes, observed frequencies of pathologic complete response, pathologic partial response, and no response were 2, 5, and 0; 1, 4, and 0; and 1, 1, and 3, respectively. Responders (pathologic complete response and pathologic partial response) had the largest reductions in choline signal-to-noise ratio (35%, from 7.2 ± 2.3 to 4.6 ± 2; P < .01) compared to nonresponders (11%, from 8.4 ± 2.7 to 7.5 ± 3.6; P = .13) after the first cycle. Total tissue sodium concentration significantly decreased in responders (27%, from 66 ± 18 to 48.4 ± 8 mmol/L; P = .01), while there was little change in nonresponders (51.7 ± 7.6 to 56.5 ± 1.6 mmol/L; P = .50). Lesion volume decreased in responders (40%, from 78 ± 78 to 46 ± 51 mm³; P = .01) and nonresponders (21%, from 100 ± 104 to 79.2 ± 87 mm³; P = .23) after the first cycle. The largest reduction in Response Evaluation Criteria in Solid Tumors occurred after the first treatment in responders (18%, from 24.5 ± 20 to 20.2 ± 18 mm; P = .01), with a slight decrease in tumor diameter noted in nonresponders (17%, from 23 ± 19 to 19.2 ± 19.1 mm; P = .80). CONCLUSIONS: Multiparametric and multinuclear imaging parameters were significantly reduced after the first cycle of preoperative systemic therapy in responders, specifically, choline signal-to-noise ratio and sodium. These new surrogate radiologic biomarkers maybe able to predict and provide a platform for potential adaptive therapy in patients.

Statement of the science concerning locoregional treatments after preoperative chemotherapy for breast cancer: a National Cancer Institute conference.

PURPOSE: To review the state of the science with respect to diagnostic imaging and locoregional therapy for patients with breast cancer receiving preoperative chemotherapy. METHODS: Published data relevant to clinical staging, monitoring of tumor response, and locoregional therapy for patients with breast cancer treated with preoperative chemotherapy were reviewed. RESULTS: High-quality data from prospective randomized trials are limited. Available data suggest that locoregional therapy decisions should be based on both the pretreatment clinical extent of disease and the pathologic extent of the disease after chemotherapy. Accordingly, physical examination and imaging studies that accurately define the initial extent of disease are required before treatment. Sentinel lymph node biopsy can be performed either before or after preoperative chemotherapy for patients with clinical N0 disease. The success of breast conservation after preoperative chemotherapy depends on careful patient selection and achieving negative surgical margins. Adjuvant breast radiation is indicated for all patients treated with breast conservation. For patients treated with mastectomy, chest-wall and regional nodal radiation should be considered for those who present with clinical stage III disease or have histologically positive lymph nodes after preoperative chemotherapy. Additional prospective studies are needed to determine the value of postmastectomy radiation for patients with stage II breast cancer who have negative lymph nodes after chemotherapy. CONCLUSION: The increased use of preoperative chemotherapy has raised new questions concerning the optimal methods to stage and monitor disease response to treatment and how to optimize locoregional treatment. The available evidence suggests that a multidisciplinary approach improves outcomes.

Elevated tissue sodium concentration in malignant breast lesions detected with non-invasive 23Na MRI.

BACKGROUND: The hypothesis that physiological and biochemical changes associated with proliferating malignant tumors may cause an increase in total tissue sodium concentration (TSC) was tested with non-invasive, quantitative sodium ((23)Na) magnetic resonance imaging (MRI) in patients with benign and malignant breast tumors. METHODS: (23)Na and (1)H MRI of the breast was performed on 22 women with suspicious breast lesions (> or =1 cm) at 1.5 Tesla. A commercial proton ((1)H) phased array breast coil and custom solenoidal (23)Na coil were used to acquire (1)H and (23)Na images during the same MRI examination. Quantitative 3-dimensional (23)Na projection imaging was implemented with negligible signal loss from MRI relaxation, or from radio-frequency field inhomogeneity, in less than 15 min. Co-registered (1)H and (23)Na images permitted quantification of TSC in normal and suspicious tissues on the basis of (1)H MRI contrast enhancement and anatomy, with histology confirmed by biopsy. RESULTS: Sodium concentrations were consistently elevated in (N = 19) histologically proven malignant breast lesions by an average of 63% compared to glandular tissue. The increase in sodium concentration in malignant tissue was highly significant compared to unaffected glandular tissue (P < 0.0001, paired t-test), adipose tissue, and TSC in three patients with benign lesions. CONCLUSION: Elevated TSC in breast lesions measured by non-invasive (23)Na MRI appears to be a cellular-level indicator associated with malignancy. This method may have potential to improve the specificity of breast MRI with only a modest increase in scan time per patient.