ASCO studies pose question: Do brain metastases in patients with HER2+ breast ca affect overall survival?

ASCO—Recent data suggest that HER2 positivity predicts for the development of CNS metastases in breast cancer patients. Studies presented at the ASCO 2007 annual meeting found that risk of brain metastases is indeed increased in HER2-positive patients but does not appear to compromise survival.

Trastuzumab and survival

In a retrospective study, M.D. Anderson Cancer Center investigators (abstract 1018) evaluated time to CNS metastasis, death, and death subsequent to brain metastases in relation to trastuzumab (Herceptin) treatment in a population of HER2-positive patients.

The analysis included 231 patients who received trastuzumab as first-line therapy and 61 who were treated before trastuzumab was available and therefore did not receive the drug.

At 2 years, 41% of trastuzumab-treated patients had developed brain metastases and 34% had died, compared with 20% and 44%, respectively, of the non-trastuzumab-treated patients. Median survival was 33.5 months for the trastuzumab patients, compared with 29.4 months for the controls.

After adjusting for other prognostic variables, patients who received trastuzumab had nearly a threefold higher risk of developing CNS metastases (HR 2.81, P < .03), compared with patients not receiving trastuzumab.

"Improved survival among patients treated with first-line trastuzumab may explain, in part, the increased incidence of brain metastases in this group, as more patients survived long enough to develop brain metastases," Mary C. Pinder, MD, reported.

Among those patients who did develop brain metastases, survival after the brain metastases diagnosis was better for the trastuzumab-treated patients than the patients who did not receive trastuzumab (HR 0.25, P = .01).

Brain mets and survival

Survival was also not affected by the development of brain metastases in a study from the University of Alabama at Birmingham (abstract 1016), reported by Stephen M. Sawrie II, MD, PhD.

In this retrospective study of 50 patients with primary breast cancer who developed brain metastases, HER2-positive patients had a greater risk of developing brain metastases, but their overall survival was better than that of the HER2-negative patients. Dr. Sawrie noted that all but one of the HER2-positive patients received trastuzumab.

HER2-positivity and the occurrence of three or fewer initial brain lesions were independently associated with better overall survival from time of the CNS diagnosis, Dr. Sawrie reported.

Median survival in HER2-positive patients was 65 weeks, compared with 33 weeks for HER2-negative patients; 1-year survival was 87% vs 44%. One-year survival was 80% for those with three or fewer brain lesions vs 39% for those with more than three.

Again, the researchers credited "improved extracranial control provided by trastuzumab" for the better overall survival in the HER2-positive patients.

A Canadian study, presented by Shailendra Verma, MD, Ottawa Hospital Regional Cancer Center, also found that the development of CNS metastases did not shorten survival time (abstract 1017).

The study included 100 patients with HER2-positive metastatic breast cancer treated with trastuzumab, 52 who developed CNS metastases and 48 who did not. There was no significant difference in median survival between patients who did not develop CNS metastases vs those who did (2.7 years vs 3.0 years).

The study also suggested an overall survival advantage for patients with brain metastases treated with combined surgery and radiation therapy, compared with radiation alone (29.9 months vs 7.4 months, P = .04)

Genetic predisposition

It is possible that certain patients are predisposed to developing CNS metastases, according to research from Baylor College of Medicine (abstract 1019). In a genetic analysis that compared breast cancer patients with CNS metastases and those without, Yee-Lu Tham, MD, and colleagues identified 354 genes that were more highly expressed in primary breast tumors from patients who developed brain metastasis.

No effect of early diagnosis

Polish researchers showed that early diagnosis of these brain metastases does not improve survival, even when patients receive treatment before symptoms are present (abstract 1015). Anna Niwinska, PhD, and colleagues from The Maria Sklodowska-Curie Memorial Cancer Center, Warsaw, screened 80 metastatic HER2-positive patients with MRI of the brain every 3 months and detected occult metastases in 29, who were treated with whole brain radiotherapy. These patients were compared with 48 who were treated for symptomatic brain metastases.

Median overall survival was the same in both groups: 53 months for the asymptomatic patients vs 52 months for the symptomatic patients. Median survival after the diagnosis of brain metastases was also the same: 9 months vs 9.3 months. However, brain lesions as the cause of death was significantly higher in the patients treated only after symptoms developed: 48% vs 16% for those with asymptomatic brain lesions. Patients treated before symptoms developed also had improved quality of life due to a lower rate of neurological complications. "Early treatment of asymptomatic disease reduced cerebral deaths but not overall deaths," Dr. Niwinska concluded.