NEW RESEARCH: HER-2/neu overexpression in UPSC, and promising treatment with Herceptin

My chemo-oncologist said today that, with HERCEPTIN, HER-2neu overexpression is no longer the 'poor prognosis indicator' it used to be for endometrial cancers, and that he was confident he could get insurance approval to cover Herceptin for any UPSC patient who had assay pathology that showed HER-2neu overexpression. So, UPSC Sisters, GET THOSE ASSAYS if you can, because this article makes me believe that you NEED Herceptin if you are +2 or +3:


Overexpression of HER-2/Neu in Uterine Serous Papillary Cancer

Department of Obstetrics and Gynecology, Division of Gynecologic Oncology [A. S., S. B., M. P., D. D., T. O., G. P.], Departments of Pathology [M. G.], Medicine [J. A., L. H.], and Microbiology and Immunology [M. J. C.], University of Arkansas, Little Rock, Arkansas 72205-7199, and Division of Gynecologic Oncology, University of Brescia, 25123 Brescia, Italy [A. S., S. B., M. P., S. P.]

Purpose: Uterine serous papillary carcinoma (USPC) is a highly aggressive variant of endometrial cancer and histologically similar to high-grade ovarian cancer. HER-2/neu, the transmembrane receptor encoded by the c-erbB2 gene, is overexpressed by immunohistology in ∼25% of ovarian cancers. In this study, we have evaluated the expression of HER-2/neu in several fresh, established, paraffin-embedded, fixed USPCs. In addition, we have tested the sensitivity of USPC cells to Herceptin treatment.

Experimental Design: Ten consecutive USPC specimens were assessed by immunohistochemistry for the intensity of expression of HER-2/neu. In addition, three USPC cell lines were analyzed for expression of HER-2/neu by flow cytometry as well as for sensitivity to Herceptin-mediated, complement-dependent cytotoxicity, antibody-dependent cellular cytotoxicity (ADCC), and inhibition of cell proliferation.

Results: Eight of 10 (80%) of the USPCs assessed immunohistochemically for the intensity of expression of HER-2/neu stained heavily for HER-2/neu (2+ to 3+). Fresh and established primary USPC cell lines were found to express significantly more HER-2/neu receptor by flow cytometry (on the average, 10-fold greater) when compared with HER-2/neu-positive primary or established breast and ovarian cancer cell lines (P < 0.001). Importantly, although these USPC cell lines were resistant to chemotherapy in vivo and to natural killer- and complement-mediated cytotoxicity in vitro, they were found to be highly sensitive to Herceptin-mediated ADCC. USPC cell proliferation was also inhibited by Herceptin. A significant enhancement of ADCC was demonstrated when effector cells were exposed to low doses of IL-2 in vitro. Physiological concentrations of human serum IgG did not inhibit Herceptin-mediated ADCC against USPC.

Conclusions: On the basis of these findings and previous reports showing a positive in vivo correlation between efficacy of Herceptin therapy and the level of HER-2/neu overexpression by tumor cells, we propose that Herceptin might be a novel and attractive therapeutic strategy in patients harboring chemotherapy-resistant, recurrent, or metastatic USPC.
In the clinical setting, high levels of HER-2/neu in tumor tissue have been associated with shorter patient survival (13, 14, 15) , resistance to antiestrogens (27) and chemotherapeutic drugs (13, 14, 15) , and resistance to tumor necrosis factor-α, activated macrophages, and lymphokine-activated killer cells (28) .

In conclusion, we show that HER-2/neu is highly expressed by USPCs, and we further demonstrate that USPC cells are exquisitely sensitive to Herceptin-mediated ADCC. On the basis of these findings and previous evidence showing a correlation between efficacy of Herceptin therapy in direct proportion to the HER-2/neu overexpression on tumor cells, we postulate that Herceptin might be a novel and attractive therapeutic strategy in USPC patients either for the prevention of recurrence after surgical treatment or for the treatment of metastatic disease. The future design and implementation of clinical trials in this regard will ultimately determine the validity of this approach.

for full article & references:
http://clincancerres.aacrjournals.org/content/8/5/1271.full