Identification of Selective Lead Compounds for Treatment of High-Ploidy Breast Cancer.

Increased ploidy is common in tumors but treatments for tumors with excess chromosome sets are not available. Here, we characterize high-ploidy breast cancers and identify potential anticancer compounds selective for the high-ploidy state. Among 354 human breast cancers, 10% have mean chromosome copy number exceeding 3, and this is most common in triple-negative and HER2-positive types. Women with high-ploidy breast cancers have higher risk of recurrence and death in two patient cohorts, demonstrating that it represents an important group for improved treatment. Because high-ploidy cancers are aneuploid, rather than triploid or tetraploid, we devised a two-step screen to identify selective compounds. The screen was designed to assure both external validity on diverse karyotypic backgrounds and specificity for high-ploidy cell types. This screen identified novel therapies specific to high-ploidy cells. First, we discovered 8-azaguanine, an antimetabolite that is activated by hypoxanthine phosphoribosyltransferase 1 (HPRT1), suggesting an elevated gene-dosage of HPRT1 in high-ploidy tumors can control sensitivity to this drug. Second, we discovered a novel compound, 2,3-diphenylbenzo[g]quinoxaline-5,10-dione (DPBQ). DPBQ activates p53 and triggers apoptosis in a polyploid-specific manner, but does not inhibit topoisomerase or bind DNA. Mechanistic analysis demonstrates that DPBQ elicits a hypoxia gene signature and its effect is replicated, in part, by enhancing oxidative stress. Structure-function analysis defines the core benzo[g]quinoxaline-5,10 dione as being necessary for the polyploid-specific effects of DPBQ. We conclude that polyploid breast cancers represent a high-risk subgroup and that DPBQ provides a functional core to develop polyploid-selective therapy. Mol Cancer Ther; 15(1); 48-59. ©2015 AACR.

Metastasis of primary lung carcinoma to the breast: a systematic review of the literature.

BACKGROUND: The purpose of this systematic review was to summarize previously published case reports of primary lung carcinoma metastasis to the breast to assess common clinical and pathologic features and management strategies. MATERIALS AND METHODS: Case reports describing breast metastasis of primary lung carcinoma were systematically evaluated in MEDLINE and EMBASE. RESULTS: Thirty-one reported cases of non-small-cell lung carcinoma (NSCLC) metastasized to the breast were identified, along with eight cases of small-cell lung carcinoma. Sixty-seven percent of reported NSCLC metastases to the breast were detected metachronously with the primary lung abnormality, whereas 80% of small-cell lung carcinoma breast metastases appeared synchronously. Thyroid transcription factor 1 was found to be expressed in 58% of total NSCLC breast metastases, including 83% of those of adenocarcinoma origin. Therapeutic strategies among NSCLC cases varied widely, and only 36% of NSCLC breast metastasis patients were administered chemotherapy. Additional sites of metastasis in these cases are summarized as well. CONCLUSIONS: It is recommended to include metastatic lung cancer in the differential diagnosis of patients presenting with a breast abnormality in the context of a suspected lung cancer. Thyroid transcription factor 1 expression should be examined in these cases. The metachronous versus synchronous nature of lung carcinoma metastasis to the breast has consequences for both detection of the primary and secondary lesions and patient outlook. Clinical correlation is vital to effective management of the care of patients harboring these atypical secondary lesions.

Compression-dependent viscoelastic behavior of human cervix tissue.

We have characterized the viscoelastic properties of human cervical tissue through a range of precompressional loads and testing frequencies. Mechanical testing is necessary to develop robust elasticity-based techniques for the diagnosis of cervical abnormalities. The storage modulus (E') and material damping (tan 6) were measured in 13 patients, 40 to 76 years old. Our results showed that E' increased monotonically from approximately 4.7 to 6.3 kPa over the precompression range (1-6%) for a testing frequency of 1 Hz. Increases in precompressions of 4% or greater significantly increased E' obtained after dynamic compression testing when data were normalized to 1% precompression. Tan delta remained fairly constant (approximately 0.35) and was not significantly affected by changes in precompression. E' and tan delta increased significantly with frequency. E 'monotonically increased from 4.7 to 7.9 kPa for the 1-3% compression range (lowest precompression for 2% amplitude) and from 6.3 to 10.3 kPa for the 6-8% range (highest precompression for 2% amplitude) when increasing frequency from 1 to 30 Hz. Tan delta increased montonically from 0.35 to 0.45 for 2% amplitude compressions from 1 to 30 Hz regardless of initial precompression. Our results show that precompression and testing frequency must be taken into account in order to obtain consistent measurements in mechanical diagnostic tests developed for cervical abnormalities.

Fluorescence spectroscopy: an adjunct diagnostic tool to image-guided core needle biopsy of the breast.

We explored the use of a fiber-optic probe for in vivo fluorescence spectroscopy of breast tissues during percutaneous image-guided breast biopsy. A total of 121 biopsy samples with accompanying histological diagnosis were obtained clinically and investigated in this study. The tissue spectra were analyzed using partial least-squares analysis and represented using a set of principal components (PCs) with dramatically reduced data dimension. For nonmalignant tissue samples, a set of PCs that account for the largest amount of variance in the spectra displayed correlation with the percent tissue composition. For all tissue samples, a set of PCs was identified using a Wilcoxon rank-sum test as showing statistically significant differences between: 1) malignant and fibrous/benign; 2) malignant and adipose; and 3) malignant and nonmalignant breast samples. These PCs were used to distinguish malignant from other nonmalignant tissue types using a binary classification scheme based on both linear and nonlinear support vector machine (SVM) and logistic regression (LR). For the sample set investigated in this study, the SVM classifier provided a cross-validated sensitivity and specificity of up to 81% and 87%, respectively, for discrimination between malignant and fibrous/benign samples, and up to 81% and 81%, respectively, for discriminating between malignant and adipose samples. Classification based on LR was used to generate receiver operator curves with an area under the curve (AUC) of 0.87 for discriminating malignant versus fibrous/benign tissues, and an AUC of 0.84 for discriminating malignant from adipose tissue samples. This study demonstrates the feasibility of performing fluorescence spectroscopy during clinical core needle breast biopsy, and the potential of this technique for identifying breast malignancy in vivo.

Feasibility of near-infrared diffuse optical spectroscopy on patients undergoing imageguided core-needle biopsy.

We describe a side-firing fiber optic sensor based on near-infrared spectroscopy for guiding core needle biopsy diagnosis of breast cancer. The sensor is composed of three side firing optical fibers (two source fibers and one detection fiber), providing two source-detector separations. The entire assembly is inserted into a core biopsy needle, allowing for sampling to occur at the biopsy site. A multi-wavelength frequency-domain near-infrared instrument is used to collect diffuse reflectance in the breast tissue through an aperture on the biopsy needle before the tissue is removed for histology. Preliminary in vivo measurements performed on 10 normal or benign breast tissues from 5 women undergoing stereo- or ultrasound-guided core needle biopsy show the ability of the system to determine tissue optical properties and constituent concentrations, which are correlated with breast tissue composition derived from histopathology.