Annals of Oncology Advance Access originally published online on January 10, 2005
Annals of Oncology 2005 16(3):516-517; doi:10.1093/annonc/mdi078
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© 2005 European Society for Medical Oncology
Letter to the Editor |
Can HER2 overexpression predict response to pegylated liposomal doxorubicin in metastatic breast cancer patients?
We conducted a phase II clinical trial to determine the clinical efficacy and safety of pegylated liposomal doxorubicin in combination with gemcitabine as a first- or second-line treatment option in patients with metastatic breast cancer [1
]. Based on a previous phase II study [2], the recommended dose was pegylated liposomal doxorubicin 25 mg/m2 intravenously (i.v.) on day 1 and gemcitabine 800 mg/m2 i.v. on days 1 and 8, every 21 days. A total of 41 patients were entered into the study between February 2003 and April 2004. The demographic and baseline clinical characteristics of all patients are listed in Table 1. Forty-one patients were assessable for response. The overall objective response rate (ORR) was 51% [95% confidence interval (CI) 35.9% to 66.5%], with one complete response (CR) (2.5%) and 20 partial responses (PRs) (48%). Eleven patients (27%) had evidence of stable disease (SD), and the remaining nine patients had disease progression (22%).
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Nineteen women had HER2-overexpressing (2+/3+; Dako Herceptest) breast tumors, while in the other 19 patients breast cancer did not overexpress HER2 (0/1+). HER2 overexpression score 2+ showed amplification at the DNA level detected by fluorescence in situ hybridization. In three patients HER2 expression was not assessed. Concerning patients with HER2-positive tumors, 68% experienced a response (13 patients; one CR and 12 PRs), while 15.7% had evidence of SD (three patients) and 15.7% (three patients) had disease progression. Conversely, among women with HER2-negative tumors, the ORR was half that observed in HER2-positive cases (31.5%, all PRs), with a rate of SD and PD of 42% (eight patients) and 26% (five patients), respectively. Sixty-one per cent of patients with HER2-positive disease were endocrine responsive (estrogen receptor and/or progesterone receptor positive tumors). Among 13 women who achieved a response to pegylated liposomal doxorubicin plus gemcitabine combination, seven were chemotherapy naïve for metastatic disease, while six had previously received chemotherapy. Responses were also observed in six out of 13 patients with previous anthracycline exposure, with a PR rate of 46%.
No data on the predictive value of HER2 expression regarding response to gemcitabine in breast cancer are currently available. It has been reported that the gemcitabine–cisplatin interaction is more active than the etoposide–cisplatin interaction in lung cancer cells with high p185neu expression [3]. Elevated levels of HER2 extracellular domain adversely affect the efficacy of paclitaxel plus gemcitabine in advanced breast carcinoma [4].
Our findings seem to support, even considering the low number of patients recruited, a positive interaction between HER2 overexpression and sensitivity to pegylated liposomal doxorubicin, substantially confirming the sensitivity of HER2-positive tumors to doxorubicin described previously [5]. However, considering the large use of liposomal doxorubicin or gemcitabine as single agent or in combination with other drugs in advanced breast cancer, particularly in elderly patients, it would be useful to predict the response to chemotherapy according to the HER2 expression. Moreover, since trastuzumab plus pegylated liposomal doxorubicin seems to be active and safe, these findings could provide the rationale for evaluating this combination in large scale investigations, considering the similar efficacy and improved safety profile of pegylated liposomal doxorubicin in comparison with conventional doxorubicin.
Division of Medical Oncology A, Regina Elena Cancer Institute, Via Elio Chianesi 53, 00144 Rome, Italy
* Email: gia.fer{at}flashnet.it or gia.fer{at}flashnet.it
References
1. Fabi A, Papaldo P, Ciccarese M et al. Pegylated liposomal doxorubicin (PLD) and gemcitabine (G) in metastatic breast cancer (MBC) patients: A phase II study. Proc Am Soc Clin Oncol 2004; 23: 79 (Abstr 813).
2. Rivera E, Valero V, Arun B et al. Phase II study of pegylated liposomal doxorubicin in combination with gemcitabine in patients with metastatic breast cancer. J Clin Oncol 2003; 21: 3249–3254.
3. Tsai CM, Chang KT, Chen JY et al. Cytotoxic effects of gemcitabine-containing regimens against human non-small cell lung cancer cell lines which express different levels of p185neu. Cancer Res 1996; 56: 794–801.
4. Colomer R, Llombart-Cussac A, Lluch A et al. Biweekly paclitaxel plus gemcitabine in advanced breast cancer: phase II trial and predictive value of HER2 extracellular domain. Ann Oncol 2004; 15: 201–206.
5. Mass R. The role of HER-2 expression in predicting response to therapy in breast cancer. Semin Oncol 2000; 27 (6 Suppl 11): 46–52.[Web of Science][Medline]
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