Risk of Developing Brain Metastases in Patients with Metastatic Breast Cancer

Abstract & Commentary

By William B. Ershler, MD

Synopsis: In a retrospective analysis of risk factors for the development of cerebral metastases in patients with known metastatic breast cancer, several factors including ER, HER-2, patient age, and site of first metastatic recurrence were found to be predicted. Using a cumulative incidence model employing competing-risk regression analysis, small initial tumor size, and the absence of metastatic disease at the time of diagnosis appeared to be independent risk factors.

Source:Heitz F, et al. Cerebral metastases in metastatic breast cancer: Disease-specific risk factors and survival. Ann Oncol 2011;22: 1571-1581.

For patients with existing metastatic disease from primary breast cancer, the new development of cerebral metastases (CM) predicts shortened survival.1 For all patients with newly diagnosed, operable breast cancer, the likelihood of developing CM is approximately 5%,2 but for all those who develop metastatic disease at sites other than the brain, the subsequent development of CM is considerably higher, ranging from 10%-42%.3,4 Thus, the identification of those at high risk for developing CM is warranted not only to adjust follow-up care but also for the investigation of preventive strategies. For example, with small cell lung cancer, a disease in which there is a high risk for the development of CM, prophylactic whole brain irradiation has been shown to reduce the occurrence of brain metastases and prolong survival.5

To identify risk factors associated with the development of CM in patients with metastatic breast cancer, Heitz and colleagues from Wiesbaden, Germany, performed a retrospective analysis of their institution's experience with CM occurring in patients with known metastatic disease. Their analysis, which included 668 patients with metastatic breast cancer treated between 1998 and 2008, examined cumulative incidences and employed multivariable regression analyses.

Of the 668 patients with metastatic disease, 49 were excluded for a variety of reasons but primarily because they presented with CM as their initial metastatic site. Of the remainder, 69% presented with a single metastatic site, bone being most common. The median follow-up for all patients was 10.8 years from diagnosis of breast cancer and 4.0 years from the first distant metastasis. The median distant-disease-free survival (DDFS) was 2.2 years. Of the 626 patients, 66 (11%) developed CM whereas 320 (51.1%) had died without known CM. Thus, there were 240 patients who had not developed CM and had not died.

Within this population of women with metastatic breast cancer, the estimated probability for CM was 5%, 12%, and 15% at 1, 5, and 10 years. In contrast, the probability of death without CM was 21%, 61%, and 76%, respectively at those same time points. In univariate analysis a number of factors were associated with the development of CM. These included small primary tumor size, ER and HER2 status, ductal histology, lung and lymph node metastases, younger age, and initial M0 status. Of these, only HER2, initial M0 status, and younger age proved independent predictors by multivariate analysis. As expected, for patients with metastatic breast cancer, survival was shorter for those who developed CM (24 months) compared to those with no CM (33.6 months).


This is a retrospective analysis from a single institution, subject to the usual biases of this type of review. However, the sample size is substantial and the results generally confirm earlier reports from smaller series,4,6,7 which more or less suggested the importance of ER, HER2 status, young age, and the presence of lung metastases in predicting the occurrence of CM. The value added in the current report is by virtue of the statistical methodology undertaken including cumulative-incidence and competing risk-regression analysis.8 This method accounts for the large portion of patients with aggressive but non-cerebral metastatic disease resulting in death before CM would have become apparent. Thus, the subset of patients who presented with smaller tumors, and particularly those who were M0 at the time of initial diagnosis, once diagnosed with distant metastases were at greater risk for developing CM.

It is by no means settled that preventive strategies to reduce CM would prolong life or even prevent the occurrence of brain metastases in high-risk breast cancer. In fact, there are at least two trials employing prophylactic whole brain irradiation in HER-2 positive patients that currently are underway. The current report would suggest that other risk factors might be examined to define those breast cancer patients who might benefit from similar intervention.


1. Sanna G, et al. Brain metastases in patients with advanced breast cancer. Anticancer Res 2007;27:2865-2869.

2. Barnholtz-Sloan JS, et al. Incidence proportions of brain metastases in patients diagnosed (1973 to 2001) in the Metropolitan Detroit Cancer Surveillance System. J Clin Oncol 2004;22:2865-2872.

3. Heitz F, et al. Triple-negative and HER2-overexpressing breast cancers exhibit an elevated risk and an earlier occurrence of cerebral metastases. Eur J Cancer 2009;45:2792-2798.

4. Lin NU, et al. CNS metastases in breast cancer. J Clin Oncol 2004;22:3608-3617.

5. Auperin A, et al. Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. Prophylactic Cranial Irradiation Overview Collaborative Group. N Engl J Med 1999;341:476-484.

6. Evans AJ, et al. Brain metastases from breast cancer: Identification of a high-risk group. Clin Oncol (R Coll Radiol) 2004;16:345-349.

7. Slimane K, et al. Risk factors for brain relapse in patients with metastatic breast cancer. Ann Oncol 2004;15:1640-1644.

8. Fine J, Gray R. A proportional hazards model for the subdistribution of a competing risk. J Am Stat Assoc 1999;94:496-509.