SWOG S0800 (NCI CDR0000636131): addition of bevacizumab to neoadjuvant nab-paclitaxel with dose-dense doxorubicin and cyclophosphamide improves pathologic complete response (pCR) rates in inflammatory or locally advanced breast cancer.

SWOG S0800, a randomized open-label Phase II clinical trial, compared the combination of weekly nab-paclitaxel and bevacizumab followed by dose-dense doxorubicin and cyclophosphamide (AC) with nab-paclitaxel followed or preceded by AC as neoadjuvant treatment for HER2-negative locally advanced breast cancer (LABC) or inflammatory breast cancer (IBC). Patients were randomly allocated (2:1:1) to three neoadjuvant chemotherapy arms: (1) nab-paclitaxel with concurrent bevacizumab followed by AC; (2) nab-paclitaxel followed by AC; or (3) AC followed by nab-paclitaxel. The primary endpoint was pathologic complete response (pCR) with stratification by disease type (non-IBC LABC vs. IBC) and hormone receptor status (positive vs. negative). Overall survival (OS), event-free survival (EFS), and toxicity were secondary endpoints. Analyses were intent-to-treat comparing bevacizumab to the combined control arms. A total of 215 patients were accrued including 11 % with IBC and 32 % with triple-negative breast cancer (TNBC). The addition of bevacizumab significantly increased the pCR rate overall (36 vs. 21 %; p = 0.019) and in TNBC (59 vs. 29 %; p = 0.014), but not in hormone receptor-positive disease (24 vs. 18 %; p = 0.41). Sequence of administration of nab-paclitaxel and AC did not affect the pCR rate. While no significant differences in OS or EFS were seen, a trend favored the addition of bevacizumab for EFS (p = 0.06) in TNBC. Overall, Grade 3-4 adverse events did not differ substantially by treatment arm. The addition of bevacizumab to nab-paclitaxel prior to dose-dense AC neoadjuvant chemotherapy significantly improved the pCR rate compared to chemotherapy alone in patients with triple-negative LABC/IBC and was accompanied by a trend for improved EFS. This suggests reconsideration of the role of bevacizumab in high-risk triple-negative locally advanced breast cancer.

The effect of non-steroidal anti-inflammatory drugs on osteosarcoma cells.

OBJECTIVE: Osteosarcoma (OS), an aggressive malignancy, is the most common primary bone tumor in children. Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used to reduce pain and inflammation. NSAIDs have shown to be toxic to certain malignancies such as colorectal, breast, and pancreatic cancers, but are not well-studied in OS. The purpose of this study is to assess whether ketorolac induces apoptosis in OS cells, compare this to indomethacin, which has been shown to inhibit OS proliferation, and explore the underlying mechanism. MATERIALS AND METHODS: A rat OS cell line (UMR-108) was exposed to various concentrations of ketorolac and indomethacin. Cell viability, cytotoxicity, apoptosis induction, DNA fragmentation and the expression of apoptosis-related markers were examined by MTT assay, colony formation assay, flow cytometry, agarose gel electrophoresis, and Western blot respectively. RESULTS: The results indicated that ketorolac and indomethacin could induce apoptosis of rat OS cells in a dose- and time-dependent manner. Apoptosis was confirmed by cell morphology and annexin positivity. The molecular data showed that NSAIDs affected expression of Bcl-2, survivin, and Poly (ADP-ribose) polymerase-1 (PARP). CONCLUSIONS: These findings demonstrated that NSAIDs induced apoptosis in rat OS cells in vitro. Further research focusing on the potential cytotoxicity of NSAIDs in vivo is needed.