Results from a prospective study of 1023 newly-diagnosed HER2-positive metastatic breast cancer patients show that treatment with trastuzumab(Drug information on trastuzumab) (Herceptin) and chemotherapy independently resulted in statistically significant improvement in median overall survival from the time central nervous system (CNS) metastases were diagnosed.
The large-scale multi-center study involved patients from both community and academic treatment centers. The researchers used data from the registHER study to look at potential risk factors, incidence, and outcomes, and evaluated timing of brain metastases development for HER2-positive breast cancer patients. The study results were published in Clinical Cancer Research on July 18, 2011 (doi: 10.1158/1078-0432.CCR-10-2962).
“We clearly now know that these women should get trastuzumab and potentially chemotherapy, even if cancer spreads to the brain,” said lead researcher Adam Brufsky, MD, PhD, professor of medicine and associate director of clinical investigation at the University of Pittsburg Cancer Center. “Women with HER2-positive breast cancer have a reasonable chance of living a long time with their disease, and they should be given aggressive therapy where appropriate,” he added.
Of the 1,012 women with confirmed HER2-positive tumors, 37% were found to have central nervous system (CNS) metastases. These women tended to be younger, had higher disease burden, and were more likely to have hormone receptor-negative disease. 80% of CNS metastases patients developed them after initial metastatic breast cancer (MBC) diagnosis. The median time to first CNS metastasis was 10.8 months. Treatment with trastuzumab was found to improve median overall survival (OS) after initial CNS diagnosis (17.5 months compared to 3.8 months). The hazard ratio was 0.33 (P < .001). Independently, chemotherapy was also shown to have a benefit (16.4 months median OS compared to 3.7 months for no chemotherapy. The hazard ratio was 0.64 (P = .002). Although surgery as treatment showed a trend toward decreased risk of death, it did not statistically significantly decrease death risk after CNS metastases (hazard ratio of 0.63, P = .062).
CNS Metastases in Advanced Breast Cancer
Women with advanced breast cancer have a 10% to 16% chance of developing CNS metastases. The authors point out, however, that the actual incidence is likely higher as CNS metastases are not routinely screened for but rather, are diagnosed after manifestation of symptoms. Studies have shown that HER2-positive MBC tumors are two to four times more likely to develop CNS tumors compared to HER2-negative tumors. Additional risk factors of CNS metastases include age younger than 50 years at diagnosis and having two metastatic sites at diagnosis. Researchers are currently trying to find genetic signatures that will help to predict which patients are more susceptible to brain metastases
It is likely that increased diagnosis of CNS metastases is due to improvements in systemic therapies that allow most patients to live longer. In general, patients diagnosed with CNS disease have a 20% 1-year survival. Dr. Brufsky points out that about 30% to 40% of women with MBC have some evidence of brain metastases. While some oncologists recommend MRI screenings at specific intervals to pick up early CNS disease signs, Dr. Brufsky believes “it is not yet clear whether early detection can actually change the natural history of these metastases.”
However, the mechanism of how breast cancer metastasizes to the brain is an area of active research. According to Dr. Brufsky, CNS metastasis in MBC is being studied in animal models and the current working hypothesis is that “there are certain cytokine receptor molecules on the cell surface of certain breast cancer cells which allow them to preferentially bind to brain endothelium." Which specific genes allow these cells to grow in the brain environment is also the subject of active research that will help identify key pathways to identify new targets for novel treatment developments.
The current study is both encouraging and surprising because few treatments, including chemotherapy, are able to penetrate the blood-brain barrier (BBB). Trastuzumab is not able to cross the intact BBB efficiently either.
“It is surprising that chemotherapy/trastuzumab adds to these women’s survival,” Brufsky said. “We thought that the brain metastases would be dominant in this regard no matter what therapy.”
The authors speculate that CNS disease patients may have a higher permeability of the BBB due to the physical perturbations of the tumors as well as their associated blood vessels. Additionally, it is possible that while the drug cannot pass through the BBB, the benefit seen in CNS-disease MBC patients is through prevention of micrometastases from going to the brain and forming new lesions.
Although this study is prospective, its limitation is that it is a non-randomized observational study in which patient treatment is not controlled. A follow-up randomized study to support the data reported in the current study as well as identification of factors that most affect treatment efficacy of CNS disease in HER2-positive MBC patients should further elucidate the best treatments and facilitate efficient diagnosis. The research team led by Dr. Brufsky is currently analyzing its database to find specific factors that may affect treatment efficacy in order to design follow-up trials.