Whole-Brain Radiotherapy No ‘Magic Bullet’ for Breast Cancer CNS Metastases

Recent findings have raised doubts about the promise of whole-brain radiation therapy (WBRT) against metastatic brain tumors for patients with advanced breast cancer, according to a speaker at the 34th Annual Miami Breast Cancer Conference, held March 9–12 in Miami Beach, Florida.

Survival has improved for almost all types of metastatic breast cancer. But as a result, more patients are living long enough to develop late-stage metastases of the brain, a daunting management challenge, reported Kimberly L. Blackwell, MD, of the Duke Cancer Center, Durham, North Carolina. 

Despite progress in treating HER2-positive central nervous system (CNS) metastases, the reality is that “most patients do die of CNS metastases, having very well-controlled below the neck disease,” Blackwell said.

A long-standing hope had been that WBRT could improve patient survival times. But recent clinical trial experience has tempered that optimism, Blackwell said.

For example, results from patients with lung cancer who participated in the phase III non-inferiority Quality of Life after Treatment for Brain Metastases (QUARTZ) trial were disappointing, finding no quality of life or survival benefits, Blackwell noted.

“We tend to think of non–small-cell lung cancer patients as doing worse than breast cancer, but with the introduction of immunotherapy, they’re catching up, frankly,” noted Blackwell.

WBRT offered patients with lung cancer metastasis of the brain “no benefit above palliative care,” she said.

“This is the kind of study we need to continue to do in this patient space,” Blackwell said. Such findings inform treatment decision-making and serve to temper the understandable instinct to “rush” to WBRT when patients develop symptomatic brain metastases, Blackwell explained. 

Another study, published in JAMA, found that among patients with 1 to 3 brain metastases, adding WBRT to stereotactic radiosurgery was associated with worsened cognitive deterioration after 3 months, with no overall survival benefits.

Other avenues of research might offer better hope for the future of CNS metastasis management despite the disappointing findings for WBRT, however.

“Don’t forget about traditional agents that might cross into the brain,” Blackwell urged, adding that some small molecules that are active against HER2 have demonstrated “some activity” in the brain.

“There is some evidence that before we jump to WBRT, we should think about some of these drugs,” she said, noting evidence that several newer agents, including capecitabine, CDK4/6 inhibitors, everolimus, and PARP inhibitors “all have the ability to cross the blood-brain barrier.” Several are undergoing study.

“I think we’ve moved the needle a little bit with HER2-positive disease,” Blackwell said.

For example, single-agent neratinib has shown modest anticancer activity in progressing HER2-positive brain metastases, albeit admittedly with “a bit of a lackluster response rate at 8%,” she said.

If brain metastases progress but disease is controlled elsewhere, systemic therapy should not be changed and brain metastases should be treated, she said.

The SWOG 1416 trial is currently enrolling patients with triple-negative breast cancer who have not undergone radiation therapy, Blackwell noted.

“Clinical trials offer great options for patients facing CNS metastases,” she concluded.