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Purpose: Metastatic breast cancer is a deadly disease which requires new therapeutic strategies. Endogenous TNF-related apoptosis-inducing ligand (TRAIL) functions as a metastasis suppressor by activating proapoptotic TRAIL receptors (TRAIL-R1/DR4 and/or TRAIL-R2/DR5) in transformed cells, making it an attractive pathway for antimetastatic therapies. However, it is unclear whether TRAIL-R1 or TRAIL-R2 is a better therapeutic target in metastatic breast cancer.Experimental Design: Several metastatic, triple (estrogen receptor, progesterone receptor, and HER2)-negative cancer cell lines were treated with human agonistic monoclonal antibodies targeting TRAIL-R1 (mapatumumab) or TRAIL-R2 (lexatumumab). The effects on cell viability, apoptosis, and caspase-8 activation were determined. An orthotopic model of triple-negative breast cancer in which fluorescently labeled breast cancer cells metastasize from the mammary gland to lymph nodes and lung was utilized to evaluate the effects of mapatumumab, lexatumumab, or doxorubicin on primary and metastatic tumor burden in vivo.Results: Lexatumumab was more effective than mapatumumab in activating caspase-8, inducing apoptosis and inhibiting long-term survival of metastatic cancer cells, which expressed both TRAIL-R1 and TRAIL-R2. Human mammary epithelial cells transformed by oncogenic Ras were more sensitive to lexatumumab than nontransformed cells. Lexatumumab inhibited lymph node and lung metastases more robustly than mapatumumab in an orthotopic model of triple-negative breast cancer; both agents inhibited mammary tumor growth. In addition, lexatumumab was more effective than doxorubicin at suppressing metastases at doses of doxorubicin that were associated with toxicity, even though doxorubicin reduced primary tumor burden more robustly than lexatumumab.Conclusion: Targeting TRAIL-R2 receptor may be an effective therapeutic strategy for metastatic breast cancer. Clin Cancer Res; 17(15); 5005-15. Ó2011 AACR.

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The American Society for Colposcopy and Cervical Pathology (ASCCP) has proposed high-risk human papillomavirus (HPV) testing as the "preferred" triage for women with atypical squamous cells of undetermined significance. We studied 401 atypical squamous cells of undetermined significance liquid-based cervicovaginal cytology split samples for HPV by chromogenic in situ hybridization (CISH) and by Hybrid Capture (HC) II (Digene, Gaithersburg, MD); 202 underwent HC II followed by CISH, and 199 underwent CISH followed by HC II. Of 401 vials, 101 (25.2%) were positive for HPV by 1 or more methods. HC II labeled 83 of 401 (20.7%) samples as positive, while 38 of 401 (9.5%) were positive by CISH. Positive attributes of CISH include the provision of a cytomorphologic link in assessing HPV positivity and comparative ease of use in laboratories without trained molecular diagnosticians. Greater efficacy and quantitative design are advantages of HC II. Comparing data by sequence of testing showed a lower likelihood of positive test results on the second ancillary test than on the first ancillary test, regardless of age or testing method (odds ratio, second/first = 0.58; P = .003). This finding suggests that liquid-based cervicovaginal cytology samples are not homogeneous throughout. Correlative studies with histology and polymerase chain reaction may clarify predictive values for both methods.