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    Awarded Grants
    A Novel Approach to Monitor Genetic Changes Associated with Breast Cancer Progression

    Scientific Abstract:
    We hypothesize that patients with breast cancer whose primary tumor was HER-2 gene non-amplified can acquire HER-2 gene amplification as determined by FISH analysis of their circulating tumor cells (CTCs) and that a portion of such patients can respond to trastuzumab-containing therapy. At present, patients who do not have HER-2 overexpression in their primary tumor do not receive trastuzumab-containing treatment. The primary tumor is considered the "gold standard" for making the diagnosis of HER-2 gene amplification. This assumption should be questioned because the genetically unstable clone of tumor cells is rapidly mutating giving rise to variants which are resistant to the particular chemotherapeutic regimen that was employed. Hence, it would be predicted that amplification of genes that make tumor cells more aggressive and resistant to chemotherapy will emerge with tumor progression. In patients with primary breast carcinoma, concordance between the pathologists’ evaluation of the primary tumor and FISH evaluation of CTCs was 97% (29 of 30 patients). Of the breast cancer patients whose primary tumor was HER-2 gene non-amplified, HER-2 gene amplification was present in the CTCs of 37 per cent (9 of 24) of such patients after a recurrence. Four of these patients who were far advanced and chemorefractory were treated with trastuzumab-containing therapy. Three patients responded clinically. One was moribund on admission, but now 20 months later is asymptomatic and continues to lead a normal life with ongoing targeted treatment. One patient with only 20% of her CTCs amplified had a PR after trastuzumab therapy. Testing of concordance between primary and metastatic tumor with concomitantly obtained CTCs will be extended with emphasis on metastatic tumor. Our oncologists will treat patients who have acquired HER-2 gene amplification with targeted treatment. Finally, immunofluorescence staining of Her-2 CTCs on slides allows correlation of expression and gene amplification on the same individual cell. Of 19 patients, the intensity of staining correlated with gene amplification in every patient. The long-term goal is to validate the use of CTCs for determination of changes in immunophenotype and genotype in progressive cancer such as acquisition of HER-2 gene amplification. This would ensure that patients who acquire treatable changes in their tumor will receive optimal targeted therapy.

    Lay Abstract:
    We hypothesize that patients with breast cancer whose primary tumor was HER-2 gene non-amplified can acquire HER-2 gene amplification as determined by FISH analysis of their circulating tumor cells (CTCs) and that a portion of such patients can respond to trastuzumab-containing therapy. At present, patients who do not have HER-2 overexpression in their primary tumor (the "gold standard" are believed to remain Her-2 negative as cancer progresses) do not receive trastuzumab-containing treatment. This assumption should be questioned because the genetically unstable clone of tumor cells is rapidly mutating giving rise to variants which are resistant to the particular chemotherapeutic regimen that was employed. Hence, it would be predicted that amplification of genes that make tumor cells more aggressive and resistant to chemotherapy will emerge with tumor progression. In patients with primary breast carcinoma, concordance between the pathologists’ evaluation of the primary tumor and FISH evaluation of CTCs was 97% (29 of 30 patients). Of the breast cancer patients whose primary tumor was HER-2 gene non-amplified, HER-2 gene amplification was present in the CTCs of 37 per cent (9 of 24) of such patients after a recurrence. Four of these patients who were far advanced and chemorefractory were treated with trastuzumab-containing therapy. Three patients responded clinically. One was moribund on admission, had a CR and now 20 months later is asymptomatic with continuing targeted treatment. One patient with only 20% of her CTCs HER-2 gene amplified had a PR after trastuzumab therapy. Testing of concordance between primary and metastatic tumor with concomitantly obtained CTCs will be extended with emphasis on metastatic tumor. Our oncologists will treat patients who have acquired HER-2 gene amplification with targeted treatment. Finally, immunofluorescence staining of Her-2 CTCs on slides allows correlation of expression and gene amplification on the same cell. Of 19 patients, the intensity of staining of the CTC population correlated with gene amplification in every patient. The long-term goal is to validate the use of CTCs for determination of changes in immunophenotype and genotype in progressive cancer such as acquisition of HER-2 gene amplification. This would ensure that patients who acquire treatable changes in their tumor will receive optimal targeted therapy.