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585 Background: Multiple clinicopathologic factors have been analyzed for their association with an increased risk of ipsilateral breast tumor recurrence (IBTR) following conservative surgery for D...

1039 Background: BM occur in ∼30% of BC patients (pts). BM tropism and dissemination are not well understood. We correlated tumor signatures with clin. variables and compared path. characteristics ...

796 Background: In DMBA-induced animal models of breast cancer, estrogen (E) induced expression of VEGF whereas AI therapy (Rx) had the opposite effect (Nakamura, 1996). We hypothesize that E-induc...

525 Background: The antivascular effects of antiangiogenic therapy for cancer are not well understood. Identifying clinically relevant intermediate markers for angiogenesis that might predict response has been difficult; CECs have been proposed as a marker of tumor progression and/or response to antiangiogenic therapy with bevacizumab. We performed a phase II study of erlotinib and bevacizumab in pts with MBC based on preclinical data suggesting that EGFR blockade may inhibit angiogenesis, and that combined blockade may increase anti-tumor activity. To explore markers of activity and response, we assayed CECs and CTCs at weeks 0 (baseline), 3, 9, and then Q 9 weeks. Methods: CECs were defined as CD34/31+, CD45-. Progenitor (CD133+) (CECp) and activation markers (CD106+) were also measured. For CECs, 50 ul of blood was stained with the indicated MAbs; after RBC lysis, flow cytometry (FC) was performed for total CEC and CECp. For CTCs, 20 ml of blood was subjected to immunomagnetic capture using anti-EpCAM ...

2001 Background: Aberrant VEGFR expression in breast tumor cells and EGFR expression in endothelial cells may contribute to tumor growth and progression (Baker, 2002; Kranz, 1999). Preclinical evidence suggests that EGFR blockade may inhibit angiogenesis (Hirata, 2002), and combined blockade of the VEGFR and EGFR pathways may increase anti-tumor activity in xenograft models (Jung, 2002). We performed this two stage phase II study to explore the activity of erlotinib and bevacizumab in MBC, as a phase I/II trial in lung ca showed no pharmacokinetic interaction (Mininberg, ASCO 2003). Methods: Erlotinib (150 mg orally/day) and bevacizumab (15mg/kg IV q3 weeks) is given to pts with measurable MBC following 1–2 prior chemotherapy regimens (CRx). The primary endpoint is response rate; secondary endpoints include safety and time to tumor progression. Markers of the EGFR and VEGFR pathways will be evaluated in archival tumor tissue and in pre/post treatment tumor biopsies in several pts. Levels of circulating en...

SummaryMetastasis and chemoresistance in cancer are linked phenomena, but the molecular basis for this link is unknown. We uncovered a network of paracrine signals between carcinoma, myeloid, and endothelial cells that drives both processes in breast cancer. Cancer cells that overexpress CXCL1 and 2 by transcriptional hyperactivation or 4q21 amplification are primed for survival in metastatic sites. CXCL1/2 attract CD11b+Gr1+ myeloid cells into the tumor, which produce chemokines including S100A8/9 that enhance cancer cell survival. Although chemotherapeutic agents kill cancer cells, these treatments trigger a parallel stromal reaction leading to TNF-α production by endothelial and other stromal cells. TNF-α via NF-kB heightens the CXCL1/2 expression in cancer cells, thus amplifying the CXCL1/2-S100A8/9 loop and causing chemoresistance. CXCR2 blockers break this cycle, augmenting the efficacy of chemotherapy against breast tumors and particularly against metastasis. This network of endothelial-carcinoma-myeloid signaling interactions provides a mechanism linking chemoresistance and metastasis, with opportunities for intervention.

Recent studies have suggested that breast cancer is part of the tumor spectrum in Lynch syndrome (LS). However, the frequency and significance of DNA mismatch repair (MMR) deficiency in breast carcinoma in general is unclear. Some triple-negative breast carcinomas (TNBCs) have morphologic features similar to those described in LS-associated colorectal carcinomas; therefore, we hypothesized that TNBCs might be more likely to have MMR deficiency. In this study, we tested our hypothesis in a series of 226 TNBCs along with a control series of 90 non-triple-negative tumors, utilizing DNA MMR protein immunohistochemistry followed by PCR microsatellite instability testing and MLH1 promoter methylation testing. By immunohistochemistry, we identified 4 triple-negative carcinomas (4/226, 1.8%) showing loss of MMR proteins (3 lost MLH1 and PMS2, and 1 lost MSH2 and MSH6); whereas none of the 90 non-triple-negative carcinomas showed loss of protein. Further testing of the 3 MLH1/PMS2 protein-deficient carcinomas identified 1 tumor showing high-frequency microsatellite instability and MLH1 promoter hypermethylation. All 4 MMR protein-deficient carcinomas were ductal type with high histologic and nuclear grades. Prominent lymphocytic infiltration was noted in 2 tumors. The clinical characteristics and survival outcome varied widely among the 4 patients. In conclusion, our results suggest that DNA MMR deficiency is rare in breast carcinoma, and as such, testing of breast carcinoma for the detection of LS may best be restricted to high-risk individuals only. Our data also suggest that not all MMR protein-deficient breast tumors show microsatellite instability, and MLH1 promoter methylation is the molecular basis for at least a subset of microsatellite instable breast tumors. Although MMR-deficient breast carcinomas share certain morphologic features with the more typical types of LS-associated tumors, better characterization, and a better understanding of their clinical behavior await further analysis with a larger sample size.

11000 Background: In the past decade, sequencing studies have delineated somatic mutations in human cancers. Given that cancer cells interact with their microenvironment and the presence of somatic...

89 Background: Ductal lavage (DL) is a procedure used to obtain epithelial cells from a breast duct for cytologic evaluation. Previous studies have investigated DL as a potential screening procedure for women at high-risk for cancer. The data, however, does not support a significant correlation between lavage cytology and the presence of invasive carcinoma. It is postulated that an invasive cancer causes destruction of the involved ducts which prevents direct sampling of the malignant intraductal cells. Because ductal carcinoma in-situ (DCIS) does not disrupt the breast ductal structure, DL may yield a more representative cytologic sample in patients with DCIS. Methods: Ductal lavage was performed in the affected breast of 32 women undergoing mastectomy with preoperative diagnosis of DCIS. The lavage procedure was done in the operating room after induction of general anesthesia by cannulating a duct yielding fluid on the nipple and instilling saline which was then aspirated and sent for cytologic evaluation. A cytopathologist classified each sample as insufficient cellular quantity, benign, mild atypia, marked atypia, or malignant. Results: A successful lavage was obtained from 22 (69%) of 32 women undergoing DL in the operating room. Of these 22 cytology samples; 4(18%) had an insufficient cellular quantity, 4 (18%) had mild atypia, 6 (27%) had marked atypia, and 8 (36%) had malignant cells. Twenty one of these 22 women had DCIS in the surgical mastectomy specimen. Seven (32%) patients were found to have invasive ductal cancer in addition to DCIS on final pathology. Conclusions: Our results show that DL reveals markedly atypical or malignant cytology in 64% of patients with DCIS who underwent a successful lavage procedure. As an office procedure, DL may have the ability to obtain viable ductal carcinoma cells repeatedly over time in the same patient. Thus, DL may have an important role in patients with DCIS who are involved in window trial studies investigating response to medical treatments prior to surgical intervention. Further studies to evaluate the reproducibility of the ductal lavage results in patients with DCIS are needed to confirm these findings.

•The poor prognosis of triple negative breast cancer (TNBC) relative to other biological subtypes of breast cancer, including increased risk of locoregional recurrence, has been well established. •Recently, the classic paradigm in breast cancer demonstrating locoregional equivalence of BCT to mastectomy has been questioned in patients with TNBC, with a recent study showing improved LRR with BCT vs. mastectomy.