Malignancy rates after surgical excision of discordant breast biopsies.

BACKGROUND: Vacuum-assisted core-needle biopsy (VAB) is increasingly used to perform breast biopsies instead of automated-gun core-needle biopsy (CNB). The significance of discordance between radiologic and pathologic findings has not been well established in the era of VAB predominance. This retrospective study was conducted to determine the rate of malignancy after surgical excisional biopsy (EXB) of these lesions at our two institutions. MATERIALS AND METHODS: We reviewed medical records from January 2008-June 2013 to identify female patients who underwent EXB for a Breast Imaging-Reporting and Data System (BI-RADS) 4 or 5 lesions found to be benign and discordant on CNB. Clinicopathologic data were gathered, and analysis was performed using descriptive statistics. RESULTS: A total of 8081 core biopsies were performed in the study timeframe. Six of 81 (7.4%) patients who had an EXB for a benign discordant breast lesion were found to have malignant pathology (two invasive, four in situ). Four of 63 (6.3%) lesions originally biopsied by VAB were upgraded, compared with 2 of 17 (11.8%) originally biopsied by CNB. There were no statistically significant differences in the rates of upgrade to malignancy when data were stratified by BI-RADS score or method of biopsy. CONCLUSIONS: The overall rate of malignancy after EXB of benign discordant lesions was 7.4%. Despite the widespread adoption of VAB, EXB is still warranted for clarification of discordant radiologic-pathologic findings.

Targeting Notch, a key pathway for ovarian cancer stem cells, sensitizes tumors to platinum therapy.

Chemoresistance to platinum therapy is a major obstacle that needs to be overcome in the treatment of ovarian cancer patients. The high rates and patterns of therapeutic failure seen in patients are consistent with a steady accumulation of drug-resistant cancer stem cells (CSCs). This study demonstrates that the Notch signaling pathway and Notch3 in particular are critical for the regulation of CSCs and tumor resistance to platinum. We show that Notch3 overexpression in tumor cells results in expansion of CSCs and increased platinum chemoresistance. In contrast, γ-secretase inhibitor (GSI), a Notch pathway inhibitor, depletes CSCs and increases tumor sensitivity to platinum. Similarly, a Notch3 siRNA knockdown increases the response to platinum therapy, further demonstrating that modulation of tumor chemosensitivity by GSI is Notch specific. Most importantly, the cisplatin/GSI combination is the only treatment that effectively eliminates both CSCs and the bulk of tumor cells, indicating that a dual combination targeting both populations is needed for tumor eradication. In addition, we found that the cisplatin/GSI combination therapy has a synergistic cytotoxic effect in Notch-dependent tumor cells by enhancing the DNA-damage response, G(2)/M cell-cycle arrest, and apoptosis. Based on these results, we conclude that targeting the Notch pathway could significantly increase tumor sensitivity to platinum therapy. Our study suggests important clinical applications for targeting Notch as part of novel treatment strategies upon diagnosis of ovarian cancer and at recurrence. Both platinum-resistant and platinum-sensitive relapses may benefit from such an approach as clinical data suggest that all relapses after platinum therapy are increasingly platinum resistant.

Transformation of the fallopian tube secretory epithelium leads to high-grade serous ovarian cancer in Brca;Tp53;Pten models.

High-grade serous ovarian carcinoma presents significant clinical and therapeutic challenges. Although the traditional model of carcinogenesis has focused on the ovary as a tumor initiation site, recent studies suggest that there may be additional sites of origin outside the ovary, namely the secretory cells of the fallopian tube. Our study demonstrates that high-grade serous tumors can originate in fallopian tubal secretory epithelial cells and also establishes serous tubal intraepithelial carcinoma as the precursor lesion to high-grade serous ovarian and peritoneal carcinomas in animal models targeting the Brca, Tp53, and Pten genes. These findings offer an avenue to address clinically important questions that are critical for cancer prevention and early detection in women carrying BRCA1 and BRCA2 mutations.