Management of primary resistance to gemcitabine and cisplatin (G–C) chemotherapy in metastatic bladder cancer with HER2 over-expression

D. Amsellem-Ouazana*,1, P. Beuzeboc2, M. Peyromaure1, A. Viellefond3, M. Zerbib1 and B. Debre1

Departments of 1 Urology, 2 Medical Oncology and 3 Pathology, Hôpital Cochin, Paris, France

*E-mail: d.amsellem-ouazana@cch.ap-hop-paris.fr

Recent advances in treatment of metastatic bladder cancer have not yet allowed better survival rates, although there is a decrease in toxicity [1]. HER2 over-expression could be a good aim for new targeted therapies in bladder cancer [2] as demonstrated in breast cancer [3]. The following case history may strengthen this issue.

A 51-year-old male patient, a smoker, with invasive bladder cancer and lung metastases at presentation was treated with gemcitabine and cisplatin (G–C) chemotherapy. Following three courses (G 1250 mg/m2 on days 1 and 8; C 70 mg/m2 every 21 days) he had a major progression of lung metastases together with appearance of liver metastasis. Immunohistochemistry (IHC) using monoclonal antibody CB 11 showed a 3+ score HER2 over-expression.

A second-line chemotherapy with paclitaxel (175 mg/m2) and carboplatin (area under the curve of 5) was delivered every 3 weeks together with a weekly intravenous administration of trastuzumab (initial dose of 4 mg/kg followed by 2 mg/kg for other courses). A total of six courses were performed. CT scan at 2 months demonstrated a regression of >50% of the initial size of all lung metastases and stabilization of liver metastases (some of which had regressed). Time to progression was 6 months. Transurethral resection of the bladder tumor at 6 months showed the same pattern of HER2 over-expression. The patient’s quality of life before progression allowed him to resume normal professional activities. The patient died of brain metastasis 15 months after diagnosis. The combination of trastuzumab with chemotherapy in this case shows unexpected results in primary resistance to conventional chemotherapy where response rates are minimal and short lasting.

According to recent data [4], anti-HER2 strong membrane staining (2 or 3+) rates in advanced bladder cancer are comparable to the ones usually observed in metastatic breast cancer, where trastuzumab has proven its efficacy especially in association with paclitaxel [3].

These data may suggest new perspectives in treating patients with metastatic bladder cancer and HER2 over-expression. As recommended by Hussain and James [5], new treatment modalities, especially in phase II or III trials, should include a better patient selection based on usual prognostic factors and molecular markers such as HER2. Clinical trials are ongoing in the USA and in France.

REFERENCES

1. von der Maase H, Hansen SW, Roberts JT et al. Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: results of a large, randomized, multinational, multicenter, phase III study. J Clin Oncol 2000; 18: 3068–3077.[Abstract/Free Full Text]

2. Scholl S, Beuzeboc P, Pouillart P. Targeting HER2 in other tumor types. Ann Oncol 2001; 12 (Suppl 1): S81–S87.[Medline]

3. Slamon DJ, Leyland-Jones B, Shak S et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 2001; 344: 783–792.[Abstract/Free Full Text]

4. Gandour-Edwards R, Lara PN Jr, Folkins AK et al. Does HER2/neu expression provide prognostic information in patients with advanced urothelial carcinoma? Cancer 2002; 95: 1009–1015.[CrossRef][ISI][Medline]

5. Hussain SA, James ND. The systemic treatment of advanced and metastatic bladder cancer. Lancet Oncol 2003; 4: 489–497.[CrossRef][ISI][Medline]





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