One-third of metastatic breast ca patients develop brain mets

SAN ANTONIO—About one-third of metastatic breast cancer patients with HER2 overexpression develop metastases to the brain, compared with 5% to 20% of the general metastatic breast cancer population, according to findings from a large observational study in newly diagnosed HER2-positive breast cancer.

Denise A. Yardley, MD, program director of breast cancer reserach at the Sarah Cannon Research Institute, Nashville, reported findings from the registHER study at the 2007 San Antonio Breast Cancer Symposium (abstract 6049).

RegistHER study

RegistHER is a multicenter prospective observational study of 1,023 patients, newly diagnosed with HER2-positive metastatic breast cancer, enrolled at 240 US sites from 2003 to 2006, who received treatment designed by their oncologists. The current analysis was restricted to the 768 patients diagnosed by July 1, 2005, thus allowing a median follow-up of 18 months from the occurrence of metastases at the time of data cut-off.

“Metastases in HER2-positive disease has been a big issue,” Dr. Yardley said. “This prospective study offers a unique opportunity to study the natural history of HER2-positive metastatic breast cancer and to examine treatment patterns and outcomes in a real-world setting.”

The fact that patients with HER2-positive metastatic breast cancer are more likely to develop central nervous system (CNS) metastases than those with HER2-negative disease has not been explained.

“The CNS has been a sanctuary site,” she said. “While trastuzumab(Drug information on trastuzumab) [Herceptin] provides excellent systemic control, it does not cross the blood-brain barrier.”

A surprise

There is a theory, Dr. Yardley said, that CNS disease develops more often in HER2-positive patients because these patients obtain excellent disease control from trastuzumab [Herceptin] and thus live long enough for CNS disease to develop.

“But we did not find this,” she said. “In the registry, we found that CNS events occur very early, actually, mostly within the first year of the development of metastases. This was a bit of a surprise, and contrary to what we had thought.”

The analysis found that 236 patients (30.7%) developed CNS metastases over the 18 months of follow-up. This included 52 (6.8%) who had clinically apparent CNS metastases at the time of their initial metastatic breast cancer diagnosis, and 184 (23.9%) who developed CNS metastases as a later site of disease progression.

Patients who developed CNS metastases were younger (P = .0347), more likely to be hormone-receptor negative

(P = .0044), and had a higher disease burden (based on number of metastatic sites at diagnosis) (P = .0356), compared to patients without CNS metastases, Dr. Yardley reported.

Patients without clinically apparent CNS disease at presentation and who developed it during treatment for metastatic disease had a median time to the first CNS event of 12.1 months. Among the subset who had CNS metastases as their first and only site of progression after metastatic diagnosis, time to the first event was 11.3 months.

Median survival following the diagnosis of CNS metastases was 13.9 months. But for patients who had a CNS metastasis at the time of diagnosis, median survival was 36.1 months, Dr. Yardley reported.

Median survival time is considerably higher than would be expected, she added, based on the observation that survival of patients with brain metastases in other tumors is usually 4 to 6 months. “While HER2-positive patients are preferentially getting brain metastases earlier, they have prolonged survival,” she observed.

These observations are being explored. “It could be that brain metastases disrupt the blood-brain barrier, facilitating the delivery of effective treatments such as trastuzumab to this protected site,” she said. Other factors that could be contributing to prolonged survival include the marked improvements in radiation therapy techniques and treatment options.

Many patients who develop CNS metastases are switching to lapatinib (Tykerb), a molecule that is small enough to cross the blood-brain barrier. “We are waiting to see if this will continue to change the face of this disease,” she said.