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Rich66 · 11-10-2009, 12:47 AM

J Korean Med Sci. 2009 Oct;24(5):910-7. Epub 2009 Sep 24.
Weekly paclitaxel and trastuzumab as a first-line therapy in patients with HER2-overexpressing metastatic breast cancer: magnitude of HER2/neu amplification as a predictive factor for efficacy.

Han HS, Kim JS, Park JH, Jeon YK, Lee KW, Oh DY, Kim JH, Park SY, Im SA, Kim TY, Park IA, Bang YJ.
Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea.
We evaluated the efficacy and safety of weekly paclitaxel plus trastuzumab as first-line chemotherapy in women with HER2-overexpressing metastatic breast cancer (MBC), and we investigated the prognostic factors including magnitude of HER2/neu amplification in this population. We analyzed 54 patients with HER2-overexpressing MBC that were treated with weekly paclitaxel plus trastuzumab as first-line chemotherapy from February 2004 to December 2006. At a median follow-up of 28 months, median time to progression (TTP) was 16.6 months (95% CI, 9.4 to 23.7 months) and median overall survival was 25.6 months (95% CI, 21.8 to 27.3 months). Therapy was generally well tolerated, although three patients (5.5%) experienced reversible, symptomatic heart failure. Of the 27 patients evaluable for the HER2 FISH, patients with a HER2/CEP17 ratio of < or =4.0 had significantly shorter TTP than those with a HER2/CEP17 ratio of >4.0 (10.8 vs. 23.2 months, P=0.034). A HER2/CEP17 ratio of >4.0 was identified as significant predictive factor of TTP by multivariate analysis (P=0.032). The combination of weekly paclitaxel plus trastuzumab as first-line chemotherapy is an effective regimen in patients with HER2-FISH-positive MBC. Furthermore, the magnitude of HER2 amplification is an independent predictive factor of TTP.

PMID: 19794992 [PubMed - in process]

Clin Cancer Res. 2006 Feb 1;12(3 Pt 1):904-16.
Strategies for delaying or treating in vivo acquired resistance to trastuzumab in human breast cancer xenografts.

du Manoir JM, Francia G, Man S, Mossoba M, Medin JA, Viloria-Petit A, Hicklin DJ, Emmenegger U, Kerbel RS.
Molecular and Cellular Biology Research, Sunnybrook and Women's College Health Sciences Centre, Toronto, Ontario, Canada.
PURPOSE: Acquired resistance to trastuzumab (Herceptin) is common in patients whose breast cancers show an initial response to the drug. The basis of this acquired resistance is unknown, hampering strategies to delay or treat such acquired resistance, due in part to the relative lack of appropriate in vivo tumorigenic models. EXPERIMENTAL DESIGN: We derived an erbB-2-positive variant called 231-H2N, obtained by gene transfection from the highly tumorigenic erbB-2/HER2-negative human breast cancer cell line, MDA-MB-231. Unlike MDA-MB-231, the 231-H2N variants was sensitive to trastuzumab both in vitro and especially in vivo, thus allowing selection of variant resistant to drug treatment in the latter situation after showing an initial response. RESULTS: The growth of established orthotopic tumors in severe combined immunodeficient mice was blocked for 1 month by trastuzumab, after which rapid growth resumed. These relapsing tumors were found to maintain resistance to trastuzumab, both in vitro and in vivo. We evaluated various therapeutic strategies for two purposes: (a) to delay such tumor relapses or (b) to treat acquired trastuzumab resistance once it has occurred. With respect to the former, a daily oral low-dose metronomic cyclophosphamide regimen was found to be particularly effective. With respect to the latter, an anti-epidermal growth factor receptor antibody (cetuximab) was effective as was the anti-vascular endothelial growth factor (anti-VEGF) antibody bevacizumab, which was likely related to elevated levels of VEGF detected in trastuzumab-resistant tumors. CONCLUSIONS: Our results provide a possible additional rationale for combined biological therapy using drugs that target both erbB-2/HER2 and VEGF and also suggest the potential value of combining less toxic metronomic chemotherapy regimens not only with targeted antiangiogenic agents but also with other types of drug such as trastuzumab.

PMID: 16467105 [PubMed - indexed for MEDLINE]

11-10-2009, 12:47 AM	#5
Rich66 Senior Member Join Date: Feb 2008 Location: South East Wisconsin Posts: 3,431	Re: Herceptin (Traztuzumab) J Korean Med Sci. 2009 Oct;24(5):910-7. Epub 2009 Sep 24. Weekly paclitaxel and trastuzumab as a first-line therapy in patients with HER2-overexpressing metastatic breast cancer: magnitude of HER2/neu amplification as a predictive factor for efficacy. Han HS, Kim JS, Park JH, Jeon YK, Lee KW, Oh DY, Kim JH, Park SY, Im SA, Kim TY, Park IA, Bang YJ. Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea. We evaluated the efficacy and safety of weekly paclitaxel plus trastuzumab as first-line chemotherapy in women with HER2-overexpressing metastatic breast cancer (MBC), and we investigated the prognostic factors including magnitude of HER2/neu amplification in this population. We analyzed 54 patients with HER2-overexpressing MBC that were treated with weekly paclitaxel plus trastuzumab as first-line chemotherapy from February 2004 to December 2006. At a median follow-up of 28 months, median time to progression (TTP) was 16.6 months (95% CI, 9.4 to 23.7 months) and median overall survival was 25.6 months (95% CI, 21.8 to 27.3 months). Therapy was generally well tolerated, although three patients (5.5%) experienced reversible, symptomatic heart failure. Of the 27 patients evaluable for the HER2 FISH, patients with a HER2/CEP17 ratio of < or =4.0 had significantly shorter TTP than those with a HER2/CEP17 ratio of >4.0 (10.8 vs. 23.2 months, P=0.034). A HER2/CEP17 ratio of >4.0 was identified as significant predictive factor of TTP by multivariate analysis (P=0.032). The combination of weekly paclitaxel plus trastuzumab as first-line chemotherapy is an effective regimen in patients with HER2-FISH-positive MBC. Furthermore, the magnitude of HER2 amplification is an independent predictive factor of TTP. PMID: 19794992 [PubMed - in process] Clin Cancer Res. 2006 Feb 1;12(3 Pt 1):904-16. Strategies for delaying or treating in vivo acquired resistance to trastuzumab in human breast cancer xenografts. du Manoir JM, Francia G, Man S, Mossoba M, Medin JA, Viloria-Petit A, Hicklin DJ, Emmenegger U, Kerbel RS. Molecular and Cellular Biology Research, Sunnybrook and Women's College Health Sciences Centre, Toronto, Ontario, Canada. PURPOSE: Acquired resistance to trastuzumab (Herceptin) is common in patients whose breast cancers show an initial response to the drug. The basis of this acquired resistance is unknown, hampering strategies to delay or treat such acquired resistance, due in part to the relative lack of appropriate in vivo tumorigenic models. EXPERIMENTAL DESIGN: We derived an erbB-2-positive variant called 231-H2N, obtained by gene transfection from the highly tumorigenic erbB-2/HER2-negative human breast cancer cell line, MDA-MB-231. Unlike MDA-MB-231, the 231-H2N variants was sensitive to trastuzumab both in vitro and especially in vivo, thus allowing selection of variant resistant to drug treatment in the latter situation after showing an initial response. RESULTS: The growth of established orthotopic tumors in severe combined immunodeficient mice was blocked for 1 month by trastuzumab, after which rapid growth resumed. These relapsing tumors were found to maintain resistance to trastuzumab, both in vitro and in vivo. We evaluated various therapeutic strategies for two purposes: (a) to delay such tumor relapses or (b) to treat acquired trastuzumab resistance once it has occurred. With respect to the former, a daily oral low-dose metronomic cyclophosphamide regimen was found to be particularly effective. With respect to the latter, an anti-epidermal growth factor receptor antibody (cetuximab) was effective as was the anti-vascular endothelial growth factor (anti-VEGF) antibody bevacizumab, which was likely related to elevated levels of VEGF detected in trastuzumab-resistant tumors. CONCLUSIONS: Our results provide a possible additional rationale for combined biological therapy using drugs that target both erbB-2/HER2 and VEGF and also suggest the potential value of combining less toxic metronomic chemotherapy regimens not only with targeted antiangiogenic agents but also with other types of drug such as trastuzumab. PMID: 16467105 [PubMed - indexed for MEDLINE] __________________ Mom's treatment history (link)