Anti-HER2 Antibody, Trastuzumab in Patients with Recurrent or Refractory Ovarian or Primary Peritoneal Carcinoma with Overexpression of HER2
Abstract & Commentary
Synopsis: The clinical value of single-agent trastuzumab in recurrent ovarian cancer is limited by the low frequency of HER2 overexpression and low rate of objective response among patients with HER2 overexpression.
Source: Bookman MA, et al. J Clin Oncol. 2003;21: 283-290.
In a phase II clinical trial of the Gynecologic Oncology Group (GOG), Bookman and colleagues evaluated the feasibility, toxicity, and efficacy of single-agent monoclonal antibody therapy targeting the human epidermal growth factor receptor 2 (HER2)/neu receptor in ovarian and primary peritoneal cancer. Eligible patients had measurable persistent or recurrent epithelial ovarian or primary peritoneal carcinoma with 2+ or 3+ HER2 overexpression documented by immunohistochemistry. Intravenous trastuzumab was administered initially at a dose of 4 mg/kg, then weekly at 2 mg/kg. Patients without progressive disease or excessive toxicity could continue treatment indefinitely. Those with stable or responding disease at 8 weeks were offered treatment at a higher weekly dose (4 mg/kg) at time of progression. Patient sera were analyzed for the presence of the soluble extracellular domain of HER2, host antibodies against trastuzumab, and trastuzumab pharmacokinetics. A total of 837 tumor samples were screened for HER2 expression, and 95 patients (11.4%) exhibited the requisite 2+/3+ expression level. Forty-five patients, all of whom received prior chemotherapy, were entered, and 41 were deemed eligible and assessable. There were only mild expected toxicities and no treatment-related deaths. Although an elevated level of the soluble extracellular domain of HER2 was detected in 8 of 24 patients, serum HER2 was not associated with clinical outcome. There was no evidence of host antitrastuzumab antibody formation. Serum concentrations of trastuzumab gradually increased with continued therapy. An overall response rate of 7.3% included 1 complete and 2 partial responses. Median treatment duration was 8 weeks (range, 2-104 weeks), and median progression-free interval was 2.0 months. Bookman et al concluded that the clinical value of single-agent trastuzumab in recurrent ovarian cancer is limited by the low frequency of HER2 overexpression and low rate of objective response among patients with HER2 overexpression.
Comment by David M. Gershenson, MD
Over the past few years, with the completion of the Human Genome Project and the explosion of knowledge in the field of cancer biology, targeted therapeutics is foremost in the minds of both patients and oncologists. While chemotherapy is very much a "shotgun" approach, the hope for targeted therapy is that one will be able to eventually individualize therapy based on the molecular profile of each patient’s tumor. Although we are not currently near that goal, several potential targets involved in tumorigenesis have been identified. These include growth factors, oncogenes, tumor suppressor genes, and angiogenic/vascular factors. The HER-2/neu oncogene is one of the prime candidates. Abnormal expression of HER-2/neu has been reported in a number of cancers, including ovarian cancer. Initial studies suggested that approximately 30% of ovarian cancers overexpress the HER-2/neu oncogene. However, this study and several others, including our own experience, peg the overexpression rate at about 10% based on immunostaining. Therefore, HER-2/neu may not be such an attractive target for the majority of ovarian cancer patients. Furthermore, as a single agent, the monoclonal antibody to HER-2/neu had limited activity in patients with HER-2/neu overexpressing, refractory ovarian or peritoneal cancers, with a response rate of only 7.3%. This response rate is lower than the 12-15% response rate reported with trastuzumab in the treatment of metastatic breast cancer. Additionally, combinations of the monoclonal antibody plus chemotherapy have been reported to achieve response rates exceeding those for the single agents. Therefore, we may see additional studies with this agent in combination with chemotherapy for ovarian cancer patients. As Bookman et al point out, however, the low frequency of HER-2/neu overexpression may make such trials impractical.
Dr. Gershenson is Professor and Chairman, Department of Gynecology, M.D. Anderson Cancer Center, Houston, Tex.