CHICAGO—As breast cancer begins to progress, a substantial percentage of women start to overexpress the HER-2/neu gene, an indicator of poor prognosis, according to a study presented here at this year's ASCO Annual Meeting.
In fact, related research analyzing key data from the same study showed that among the putative serum markers of breast cancer examined, HER-2/neu status most accurately predicted the course of the disease.
“We found that women with breast cancer do convert from HER-2/neu negative status to positive status about the time that their disease progresses,” said Alan Lipton, MD, Professor of Medicine and Oncology at the Milton S. Hershey Medical Center of the Pennsylvania State University.
“They convert at a substantial rate—in our study 62 of 240 women tested, or about one quarter of them—and converters don't do as well as non-converters.”
In the presentations at the ASCO Annual Meeting, Dr. Lipton and his colleague Suhail Ali, MD, an oncologist at Lebanon Veterans Affairs Medical Center, which is affiliated with the Hershey Medical Center, said they performed a retrospective analysis of the serum markers obtained during the pivotal clinical study that showed the superior efficacy of letrozole over tamoxifen in treating women with advanced disease.
Among the putative serum markers of breast cancer examined, HER-2/neu status most accurately predicted the course of the disease.
Resistance to Hormonal Treatment
“Preclinical studies have demonstrated that breast cancer cells initially sensitive to tamoxifen can develop resistance to its actions following prolonged exposure,” Dr. Lipton said.
“A proposed mechanism for this hormone resistance is upregulation of the growth factor receptor HER-2/neu and activation of its downstream pathways.”
Previous work has found that HER-2/neu levels are elevated in about 28% of patients who are initially treated with first-line hormone therapy for advanced breast cancer, he said.
The researchers examined the serum of 240 women who had normal or negative baseline HER-2/neu levels—no more than 15 ng/ml of HER-2/neu—and who later had disease progression.
Thirty women who were taking letrozole and 32 women on tamoxifen showed conversion to HER-2/neu positive status at the time of disease progression.
“This upregulation of serum HER-2/neu appears to occur with equal frequency in patients treated with either an anti-estrogen or an aromatase inhibitor,” Dr. Lipton said.
He suggested that serum HER-2/neu conversion during hormone therapy deserves further study as a selection method for treatment of metastatic breast cancer patients with combined hormonal plus anti-HER-2/neu-directed therapy.
A proposed mechanism for resistance to hormonal therapy is upregulation of HER-2/neu and activation of its downstream pathways.
Barbara McAneny, MD, a medical oncologist with New Mexico Oncology Hematology Consultants in Albuquerque and the ASCO delegate to the American Medical Association's House of Delegates, commented that the study gives insight into which patients need to be treated more aggressively, and which are likely to derive more benefit from treatment with drugs such as Herceptin, which work best in women with overexpression of HER-2/neu.
Predictive Value of Markers
In the second study, Dr. Ali scrutinized the predictive value of HER-2/neu, as well as the traditional tumor markers carcinoembryonic antigen (CEA) and cancer antigen (CA) 15–3.
Multivariate analysis showed that CEA and CA 15–3 did not provide additional information that could be used in determining a breast cancer patient's prognosis.
But, elevated pretreatment serum HER-2/neu is an independent prognostic factor for reduced survival of metastatic breast cancer patients with first-line hormone therapy, Dr. Ali said.
He and his colleagues looked at pretreatment serum samples in 548 of 907 patients. In the univariate analysis, patients with elevated serum HER-2/neu had significantly reduced overall survival—they lived a median of 22.3 months, compared with patients whose level of circulating HER-2/neu was in the normal range. These patients had a median survival of 41 months—a difference that was highly significant, Dr. Ali reported.
In the univariate analysis, Dr. Ali said, patients with elevated CEA and CA 15–3 also had significantly reduced survival compared with patients with normal levels, but after the multivariate analysis was performed, only HER-2/neu retained statistical significance. These patients had an elevated hazard ratio of 1.92, he said.
Other significant prognostic factors for survival in the multivariate analysis included the number of metastatic lesions, Karnofsky performance status, disease-free interval, liver metastasis, and ethnic origin.
The study indicates that patients who are serum HER-2/neu and hormone receptor positive should be enrolled in research studies evaluating the combination of hormonal and HER-2/neu-directed therapies, Dr. Ali concluded.