Kandace P. McGuire

Effect of simultaneous inhibition of epidermal growth factor receptor and cyclooxygenase-2 in HER-2/neu-positive breast cancer.

Purpose: HER-2/erbB2/neu is overexpressed in 25% to 30% of all invasive breast cancers and is associated with an aggressive course and reduced survival. HER-2/erbB2/neu breast tumors are frequently associated with up-regulation of cyclooxygenase (COX)-2 and activation of the epidermal growth factor receptor (EGFR) pathway, which promote enhanced cell growth and resistance to apoptosis. This study investigated whether simultaneously blocking both EGFR and COX-2 pathways with ZD1839 and celecoxib, respectively, would be more effective in inhibiting cell growth and inducing apoptosis than either agent alone. Experimental Design: The effects of ZD1839, celecoxib, and their combination on cell survival, cell cycle progression, and apoptosis were determined in NMF11.2 mouse mammary tumor cells. We also investigated the potential downstream EGFR-activated pathways that are altered by simultaneous inhibition of COX-2 and EGFR. Results: Celecoxib alone and ZD1839 alone produced a concentration- and time-dependent inhibition of cell survival. Both agents combined produced supra-additive inhibitory effects on cell survival and apoptosis compared with either agent alone. This effect was associated with increased cleaved poly(ADP-ribose)polymerase and reduced protein expression of bcl-2. Phosphorylation of extracellular signal-regulated kinase 1/2 was partially blocked by ZD1839 and celecoxib alone and was completely blocked by the combination of both agents. The enhanced proapoptotic effects of the combined agents were also associated with decreased phosphorylation of Akt and increased phosphorylation of p38. Conclusions: These findings show that both COX-2 and EGFR are important targets for inhibiting survival and inducing apoptosis in breast cancer. The data suggest a potential cross-talk between COX-2 and EGFR signaling in breast cancer cells overexpressing HER-2/erbB2/neu.

Timing of sentinel lymph node biopsy and reconstruction for patients undergoing mastectomy.

Options for immediate breast reconstruction after mastectomy are directly affected by nodal status. Historically, axillary dissection has been performed simultaneously with mastectomy. The advent of sentinel lymph node biopsy (SLNB) drastically changed the trends in breast cancer surgery. SLNB is often performed at the time of mastectomy and may negate the need for a formal axillary dissection. The algorithm presented here outlines an approach where SLNB is performed as a separate outpatient operation several days prior to mastectomy when immediate reconstruction is planned. While this approach requires a separate procedure, SLNB can be performed with minimal morbidity with monitored anesthesia care and local anesthesia. The significance of this algorithm is that it allows time for complete pathologic evaluation prior to definitive surgery, eliminating the dependency on frozen section diagnosis. This method also decreases the possibility of irradiating a fresh autologous flap if radiation therapy is deemed necessary after further pathology review of the sentinel node specimen. We endorse SLNB as a separate outpatient procedure prior to definitive surgery with reconstruction, particularly latissimus dorsi myocutaneous flap. This method involves a close team approach between the breast and plastic surgeons.