How to Approach the Problem of CNS Metastasis in HER2-Positive Patients

Get Permission

Eric P. Winer, MD

If you need to treat the patient with progression in the brain after prior radiotherapy, and the patient has not received capecitabine, that [capecitabine/lapatinib] is the regimen to consider.

—Eric P. Winer, MD

Central nervous system (CNS) metastasis is a pervasive problem in the setting of HER2-positive breast cancer. While some patients can be managed easily, others are challenging, said Eric P. Winer, MD, Chief of the Division of Women’s Cancers and the Thompson Senior Investigator for Breast Cancer Research at Dana-Farber Cancer Institute, and Professor of Medicine at Harvard Medical School, Boston, who shared his perspective on treating HER2-related CNS metastasis with The ASCO Post.

Studies have consistently demonstrated that the risk of CNS involvement is high in patients with HER2-positive metastatic breast cancer. Incidence ranges from 15% to 55%, depending on length of follow-up and stringency of screening. Within the HER2-positive cohort, estrogen receptor (ER)-negative disease confers a greater risk than ER-positive disease. In a 3,000-plus patient cohort from a National Comprehensive Cancer Network database, women with ER-negative disease had a 63% increased risk over ER-positive patients, he said.

Treatment Goals

“Our treatment goals are to prolong survival, palliate neurologic symptoms, and prevent symptom progression. And we have to balance treatment-related toxicities with overall brain control and minimize the risk of ‘neurologic’ death—that is, death from the progression of the CNS metastases,” Dr. Winer said.

Balancing treatment-related toxicities with overall disease control in the breast can be difficult, especially for patients expected to live long enough to develop complications from their metastatic disease, he noted. This is where treatment individualization is important and where tumor subtype may be informative.

It is important to recognize that the natural history of brain metastases differs by disease subtype. For example, compared to patients with triple-negative breast cancer, those with HER2-positive disease have a longer time from metastatic diagnosis to CNS relapse (approximately 1 year vs < 6 months), greater control of extracranial disease at the time of CNS relapse (50% vs rarely), and longer median overall survival from the time of CNS relapse (1–2 years vs 3–5 months). However, patients with triple-negative disease rarely die as a result of CNS progression alone, whereas up to 50% of those with HER2-positive disease do, he pointed out.

Elaborating on these differences, Dr. Winer noted that patients with triple-negative breast cancer tend to develop CNS metastases earlier in their disease course. Patients with triple-negative disease have a shorter overall survival compared to those with HER2-positive disease, and treatment with radiotherapy is usually the only treatment that is needed. The vast majority of patients succumb to their systemic disease before they have progression of disease in the brain. In contrast, patients with HER2-positive disease often develop progressive CNS disease after an initial course of treatment.

“Treatment must be individualized,” Dr. Winer emphasized. “It’s very much a balancing act.”

Individualized Options

The chief treatment options for local therapy include surgery, whole-brain radiotherapy, stereotactic radiosurgery, and their various combinations, depending on the number of metastatic lesions. A number of cytotoxic, targeted, and endocrine agents are also used, but radiosensitizers have proven ineffective.

“The local therapy option depends on the extent of disease in the brain. With a single lesion, it’s usually surgery with or without stereotactic radiosurgery or whole-brain radiotherapy, and in a lesion that is not surgically amenable to resection, stereotactic radiosurgery with or without whole-brain radiotherapy,” Dr. Winer said. “For patients with more than a single metastasis but with somewhat limited disease, stereotactic radiosurgery is often considered, and for those with multiple metastases, we usually choose whole-brain radiotherapy, with or without stereotactic radiosurgery,” he added.

“There has been lively debate as to whether the patient who has received stereotactic radiosurgery for a limited number of metastases should receive whole-brain radiotherapy,” he continued. “Some believe we should give whole-brain radiotherapy to all these patients, and others strongly believe we should not.”

Whole-brain radiotherapy after stereotactic radiosurgery has not been shown to improve survival, but it can extend the time before disease in the brain progresses, he explained. The problem with whole-brain radiotherapy is that it can lead to late toxicity, including a decline in cognitive function. Such symptoms can be quite troubling to patients, but they need to be balanced against the risk of uncontrolled CNS disease.

“My experience is that patients do not want to receive whole-brain radiotherapy upfront, and they delay this as long as possible,” he added.

Therapeutic Agents

Patients with HER2-positive disease who receive local therapy as the primary approach to CNS metastasis often develop progression over the ensuing months and years. A myriad of small trials and case reports suggest that several agents can be effective in treating brain metastases, including some that would not appear to penetrate the blood-brain barrier.

Theoretically, lapatinib (Tykerb), a small-molecule tyrosine kinase inhibitor, should penetrate the CNS, and demonstrated some promise in small early trials. In a larger phase II trial the response rate was only 6% and median time to progression was 2.4 months.1 The CNS response rate to lapatinib monotherapy was similar to the systemic response rate in patients previously treated with trastuzumab (Herceptin). “Responses occurred, but they were by no means frequent,” Dr. Winer noted.

In combination with capecitabine, the data for lapatinib are more encouraging, and this has become the single most-evaluated regimen for CNS relapse. In patients with refractory disease, the CNS response rate has ranged from approximately 15% to 30%, with time to progression of 3.6 to 5.5 months in various studies.

“If you need to treat the patient with progression in the brain after prior radiotherapy, and the patient has not received capecitabine, that [capecitabine/lapatinib] is the regimen to consider,” Dr. Winer advised.

There is some indication that patients who have not received radiotherapy may respond better to this approach. This was shown in the French LANDSCAPE trial of 43 patients, in which upfront treatment with capecitabine/lapatinib yielded a 67% response rate and a median time to progression of 5.5 months, which are significantly better outcomes than seen in other studies of this

It is unknown whether this is a result of patient selection, or the possibility that disease that has not been irradiated is more sensitive to this regimen. “It raises the possibility of using systemic therapy upfront in highly selected patients, though we are not sure which patients these would be,” he added. “For most of them, you would treat with local therapy first.”

A number of agents are in development for brain metastasis, with newer anti-HER2 agents and PI3K inhibitors high on the list.

Current Approach

Dr. Winer summarized what he considers the best approach to HER2-positive CNS disease at the current time. Initial treatment is local therapy in the vast majority of patients. For patients with limited disease, surgery or stereotactic radiosurgery, with or without whole-brain radiotherapy, is recommended. For those with extensive disease, whole-brain radiotherapy, 

“In my opinion, there is no need to change systemic therapy in a patient for whom it is working,” he said. “Systemic therapy alone is acceptable in highly selected patients. The patient who did well on trastuzumab and who develops brain metastasis can stay on it. There is no need to switch to lapatinib at that point.”

Upon progression, localized disease can sometimes still be treated with local therapy. Systemic therapy, outside of a clinical trial, usually consists of capecitabine/lapatinib, but other regimens can also be effective, he said. Dr. Winer cautioned against “treating every lesion just because it’s there,” noting that many small lesions revealed by imaging can remain quiescent for an extended period, and some represent radionecrosis.

In the future, research may explain why the brain is a common site of disease spread for patients with HER2-positive breast cancer, and offer a means of better treatment, he concluded. ■

Disclosure: Dr. Winer reported no potential conflicts of interest.


1. Lin NU, Diera V, Paul D, et al: Multicenter phase II study of lapatinib in patients with brain metastases from HER2-positive breast cancer. Clin Cancer Res 15:1452-1459, 2009.

2. Bachelot TD, Romieu G, Campone M, et al: LANDSCAPE: An FNCLCC phase II study with lapatininb and capecitabine in patients with brain metastases from HER2-positive metastatic breast cancer before whole-brain radiotherapy. J Clin Oncol 29(15 suppl):Abstract 509, 2011.