Herceptin (Traztuzumab)

[Rich66]

J Clin Oncol. 2009 Nov 2. [Epub ahead of print]
Understanding the Mechanisms Behind Trastuzumab Therapy for Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer.

Spector NL, Blackwell KL.
Duke Translational Research Oncology Program, Duke University Hospital, Department of Medicine, Division of Medical Oncology; and Department of Medicine/Medical Oncology, Duke University Medical Center, Durham, NC.
PURPOSE: Targeted therapy with the humanized monoclonal antibody trastuzumab has become a mainstay for human epidermal growth factor receptor 2 (HER2) -positive breast cancer (BC). The mechanisms of action of trastuzumab have not been fully elucidated, and data available to date are reviewed here. The impact of the mechanisms of action on clinical benefit also is discussed. METHODS: An extensive literature review of trastuzumab and proposed mechanisms of action was performed. RESULTS: At least five potential extracellular and intracellular antitumor mechanisms of trastuzumab have been identified in the preclinical setting. These include activation of antibody-dependent cellular cytotoxicity, inhibition of extracellular domain cleavage, abrogation of intracellular signaling, reduction of angiogenesis, and decreased DNA repair. These effects lead to tumor cell stasis and/or death. Clinical benefit from trastuzumab-based therapy in both early and advanced BC has been demonstrated. The benefit of trastuzumab use beyond progression has also been shown, which indicates the need for continuous suppression of the HER2 pathway. Targeting both HER2, with various approaches, and other pathways may enhance the clinical benefit observed with trastuzumab and overcome potential resistance. Novel combinations include pertuzumab (a HER2 dimerization inhibitor), lapatinib (a HER1/HER2 tyrosine kinase inhibitor), bevacizumab (an antiangiogenic agent), tanespimycin (a heat shock protein inhibitor), antiestrogen therapies, and an antibody-drug conjugate (trastuzumab-DM1). CONCLUSION: Trastuzumab is the foundation of care for patients with HER2-positive BC. Emerging data from studies of other targeted agents may provide alternative treatment combinations to maximize the clinical benefit from trastuzumab and prevent or delay resistance. The continued development of trastuzumab highlights promising treatment approaches for the future.

PMID: 19884552 [PubMed - as supplied by publisher]


Cancer Res. 2009 Nov 3. [Epub ahead of print]
{beta}1-Integrin Circumvents the Antiproliferative Effects of Trastuzumab in Human Epidermal Growth Factor Receptor-2-Positive Breast Cancer.

Lesniak D, Xu Y, Deschenes J, Lai R, Thoms J, Murray D, Gosh S, Mackey JR, Sabri S, Abdulkarim B.
Departments of Experimental Oncology, Laboratory Medicine and Pathology, Radiation Oncology, Statistics and Epidemiology, and Medical Oncology, Cross Cancer Institute and University of Alberta, Edmonton, Alberta, Canada.
Resistance to trastuzumab, the monoclonal antibody targeting human epidermal growth factor receptor 2 (HER-2), is a major concern for HER-2-positive metastatic breast cancer (MBC) patients. To date, HER-2 status is the only available biomarker for selecting patients for trastuzumab-based therapy. beta(1)-Integrin, an adhesion molecule involved in cell survival and drug resistance, shares common downstream signaling elements with HER-2, such as the phosphatidylinositol 3-kinase/Akt and extracellular signal-regulated kinase-1/2 (ERK1/2) pathways. The significance of beta(1)-integrin expression in HER-2-positive breast cancer and its involvement in a patient's response to trastuzumab-based therapy are unknown. We show here that overexpression of beta(1)-integrin is an independent negative prognostic factor for tumor progression of HER-2-positive MBC patients treated with trastuzumab-based chemotherapy. Enforced overexpression of beta(1)-integrin, its small interfering RNA-induced knockdown or treatment with a beta(1)-integrin-blocking antibody in HER-2-positive breast cancer cells, identified a strong inverse relationship between expression level of beta(1)-integrin and in vitro sensitivity to trastuzumab. Notably, beta(1)-integrin overexpression increased the phosphorylation of Akt-Ser473 and ERK1/2, thereby promoting survival and mitogenic signals to bypass the antiproliferative effects of trastuzumab. Our findings show that beta(1)-integrin provides a novel independent prognostic biomarker of trastuzumab response in HER-2-positive MBC patients and suggest a new target to augment the antiproliferative effects of trastuzumab. [Cancer Res 2009;69(22):8620-8].




NOTE: tanespimycin (below) development appears to have been dropped due to expiring patent.
http://www.myelomabeacon.com/news/20...opment-halted/

Maybe other HSP90 inhibs will make it






Clin Cancer Res. 2011 May 10. [Epub ahead of print]
HSP90 Inhibition is Effective in Breast Cancer: A Phase 2 Trial of Tanespimycin (17AAG) plus Trastuzumab in Patients with HER2-Positive Metastatic Breast Cancer Progressing on Trastuzumab.

Modi S, Stopeck AT, Linden HM, Solit DB, Chandarlapaty S, Rosen N, D'Andrea G, Dickler MN, Moynahan ME, Sugarman S, Ma W, Patil S, Norton L, Hannah AL, Hudis C.

LINK

Source

Medicine, Memorial Sloan-Kettering Cancer Center.

Abstract

PURPOSE:

Hsp90 is a chaperone protein required for the stability of a variety of client proteins. 17-AAG is a natural product that binds to Hsp90 and inhibits its activity, thereby inducing the degradation of these clients. In pre-clinical studies, HER2 is one of the most sensitive known client proteins of 17-AAG. Based on these data and activity in a phase 1 study, we conducted a phase 2 study of 17-AAG (tanespimycin) with trastuzumab in advanced trastuzumab-refractory HER2 positive breast cancer.
EXPERIMENTAL DESIGN:

We enrolled patients with metastatic HER2+ breast cancer whose disease had previously progressed on trastuzumab. All patients received weekly treatment with tanespimycin at 450mg/m2 intravenously and trastuzumab at a conventional dose. Therapy was continued until disease progression. The primary endpoint was response rate by RECIST criteria.
RESULTS:

Thirty-one patients were enrolled with a median age of 53 years and a median KPS of 90%. The most common toxicities, largely grade 1, were diarrhea, fatigue, nausea and headache. The overall response rate was 22%, the clinical benefit rate (CR + PR + SD) was 59 %, the median progression-free survival was 6 months (95% CI: 4-9), and the median overall survival was 17 months (95% CI: 16-28).
CONCLUSIONS:

This is the first phase 2 study to definitively show RECIST-defined responses for 17-AAG in solid tumors. Tanespimycin plus trastuzumab has significant anti-cancer activity in patients with HER2 positive, metastatic breast cancer previously progressing on trastuzumab. Further research exploring this therapeutic interaction and the activity of HSP90 inhibitors is clearly warranted.

PMID:

21558407

[PubMed - as supplied by publisher]

[cynthia1962]

hello rich
in plan english what does this means. because I read the posting everyday day. This is what I am taking every three weeks does this trastuzumab leads to tumors. Because my mri states deep white matters due to early small vessel desease or chemotherapy. I am going to a neurologist on 11/19 because I am afraid I may have some type of tumor in my brain.

[Rich66]

This article is a description of how Herceptin works. Hopefully it is helping you. It says even if it doesn't stop your cancer 100%, it should be continued, maybe with the addition of Lapatinib (Tykerb) or other chemotherapies.

[chrisy]

Thanks Rich.

Not much new info but every time they reaffirm this (continue herceptin and shut down multiple pathways) it adds more credibility to that approach!

[Rich66]

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]