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PAC requires three strategic steps. Step I: Quantitative measurement of several targets simultaneously in the tumor. These targets, termed drug response indicators (DRI), can be evaluated by immunofluorescence utilizing labeled monoclonal antibodies and a computerized fluorescence microscope. Numerical values can be derived and normalized to a fluorescent reference standard for comparison. Step II: Establishment of statistically significant correlation of DRI expression with the cytotoxic response of tumor cells to a related drug. An in vitro indexing system was established to correlate the cytotoxic effect of each drug to the corresponding DRI measurements. Seven BC cell lines with different sensitivities to various anticancer drugs were utilized. The effect of tamoxifen, paclitaxel, trastuzumab, and doxorubicin was correlated with the DRI expression for each drug in these cell lines. The DRI are estrogen receptor, beta tubulin III, HER-2/neu and topoisomerase II, respectively. Pearson rank correlation coefficients are found ranging from 0.77 to 1 and the p values ranging from 0.005 to 0.02. Step III: Technology for obtaining cancer cells from individual cancer pts. For metastatic tumors, circulating cancer cells (CCC) from peripheral blood were obtained using a negative selection procedure (Cancer 2000: Vol. 88, no. 12, p. 2787), enumerated, and stained with labeled trastuzumab in order to quantify the HER-2/neu expression. One hundred and one BC patients (pts) were studied and 402 blood samples drawn; median number of samples drawn per pt. was 4 (1-7). CCC are related to distant metastasis; 88% of Stage IV pts. have CCC at some point during sampling. CCC numbers ranged from 1-1283 per sample. Twenty pts. had four or more of CCC to test for HER-2/neu expression and also had available tumor tissue data. In 18 pts. CCC and primary tumor data concurred (90%) with 6 HER-2/neu positive and 12 HER-2/neu negative. One pt. was HER-2/neu negative in tumor tissue but HER-2/neu positive in CCC. One patient was identified as HER-2/neu positive in tumor tissue and HER-2/neu negative in CCC. Conclusion: Therapy (trastuzumab) - diagnostics (HER-2/neu expression) coupling was the first model approved by FDA for PAC for BC. However fewer than 30% of HER-2 positive metastatic BC pts. respond to trastuzumab as single agent therapy though HER-2 negative pts. are significantly less responsive. Improvement of DRI measurements in BC tumor tissue and CCC may lead to more predictable treatment outcomes. DRI measurement from section slides cut from primary tumor tissues of BC pts. will also be reported. Supported in part by NCI SBIR Grant CA081903 awarded to CCC Diagnostics, LLC. #

[Proc Amer Assoc Cancer Res, Volume 47, 2006]