BOSTON – Although brain metastasis is a notoriously formidable foe in the battle against breast cancer, recent breakthroughs in some patient subgroups suggest a challenge to its reign of terror.
As the ranks of women living with advanced breast cancer have swelled, thanks to treatment advances that alter the natural history of the disease, so has the incidence of tumor progression in the brain, according to Dr. Nancy U. Lin. The brain is a particularly hospitable sanctuary for cancer cells because few of the current chemotherapy agents penetrate the blood-brain barrier.
Dr. Nancy U. Lin
Current strategies for managing brain metastases have not substantially altered patient outcomes, Dr. Lin told attendees at a breast cancer program sponsored by Harvard Medical School in Boston.
But improved understanding of the biology of primary tumors and the specific sensitivities of tumor subtypes to various therapies (along with the identification of mediators of CNS progression) promises to usher in a new era in the treatment – and possibly prevention – of brain metastases in breast cancer, predicted Dr. Lin of the Dana-Farber Cancer Institute and Harvard Medical School, both in Boston.
Most Common in HER2 and Triple-Negative Disease
A critical consideration in the development of treatment and prevention strategies is tumor subtype. The highest incidences of brain metastases in breast cancer occur in women with HER2-positive disease and those with triple-negative (estrogen receptor–, progesterone receptor–, and HER2-negative) disease, Dr. Lin said, noting that there is also significant variation in prognosis within these subtypes.
Although estimates for median survival after a diagnosis of brain metastasis from breast cancer have been 6 months on average in historical series, many recent series have reported a median survival of 1-2 years for metastatic breast cancer patients who are HER2-positive, she said. The median survival for patients with triple-negative disease is less than 6 months, however.
These survival differences have important management implications, Dr. Lin explained. Effective, targeted, extracranial therapies extend the survival of many HER2-positive patients relative to historical estimates, and ultimately, more than half of these patients die as a result of CNS progression. In contrast, the shorter survival of women with triple-negative disease is generally attributable to progression in both the brain and distant sites.
For this reason, she said, therapies targeting the central nervous system specifically are warranted in the HER2-positive setting, whereas improved systemic treatments that target all metastatic sites are needed for patients with triple-negative disease.
Despite advances in the understanding of brain metastasis in breast cancer, the currently available treatment options are limited; as yet, no guidelines have been published for the management of brain metastasis associated specifically with breast cancer, according to Dr. Lin.
Surgery, stereotactic radiosurgery, and whole-brain radiotherapy are potential local therapeutic options, depending on the number, size, and site of metastatic lesions, she said; conventional breast cancer chemotherapies also have demonstrated efficacy in the first-line setting.
Along with her Dana-Farber colleague, Dr. ElgeneLim, she recently published a review article outlining the range of local and systemic therapeutic considerations for this patient population (Oncology 2012 July 12 [Epub ahead of print]). First-line therapies "typically have better response rates than therapies in heavily pretreated disease, and there is a need to identify therapies that will work in CNS disease that progresses following local and systemic therapies," the authors observed.
Lapatinib Studied for CNS Penetration
Among HER2-directed therapies, the small-molecule TKI (tyrosine kinase inhibitor) lapatinib (Tykerb) continues to pique interest. Because of its micromolecular structure, the agent can achieve greater CNS penetration than can the macromolecular agents, including monoclonal antibodies.
To date, this theoretical advantage has been associated with modest clinical benefit in trials. For example, in a clinical trial of single agent lapatinib, Dr. Lin and colleagues demonstrated a 2.6% objective response and an approximately 20% clinical benefit (J. Clin. Oncol. 2008;26:1993-9).
In a trial comparing the drug in combination with capecitabine (Xeloda) or topotecan (Hycamtin) in patients with brain metastasis following radiotherapy (J. Neurooncol. 2011;105: 613-20), "the objective central nervous system response was 38%," in the lapatinib plus capecitabine arm, Dr. Lin said.
Although the study was closed early because of toxicity and lack of efficacy in the topotecan arm, the observation of CNS activity in the lapatinib-capecitabine arm was promising, as were updated results from the pivotal randomized registration trial of lapatinib, suggesting that lapatinib may delay the onset of brain metastases in breast cancer patients with HER2-positive metastatic disease (Oncologist 2010;15:924-34).
In an editorial accompanying the review article by Dr. Lim and Dr. Lin, Dr. Mark D. Pegram of Stanford (Calif.) University observed that the lapatinib data suggest that "an ‘adjuvant’ HER2-TKI immediately following primary neurosurgery and/or radiotherapy for newly diagnosed [breast cancer brain metastasis] might be a more compelling treatment strategy than waiting for measurable relapse to occur following primary local therapy for HER2-positive CNS metastasis"(Oncology 2012 July 12 [Epub ahead of print]).