Herceptin (Trastuzumab) for Breast Cancer Linked to CNS Metastases

During the past decade it has been frequently observed that patients with breast cancer treated with a taxane-containing chemotherapy regimen, either in the adjuvant setting or in the metastatic setting, presenting central nervous system (CNS) involvement as the only evidence of disease progression. More studies were therefore interested to evaluate the incidence of CNS metastases in patients with early and advanced breast cancer treated with a taxane-containing chemotherapy regimen and to identify predictive factors for CNS relapse.

More recent studies reported that breast cancer patients who received a taxane-containing chemotherapy regimen had a significantly higher incidence of CNS metastases compared with that of patients treated with a nontaxane-containing regimen (Breast Cancer Res. 2006;8(4).

There are also data indicating an increased risk for brain metastases in breast cancer patients receiving trastuzumab (Herceptin). A study from the Dana Farber Cancer Institute identified central nervous system metastases in women who receive trastuzumab-based (Herceptin) therapy for metastatic breast carcinoma. Central nervous system disease is defined as one or more brain metastases or leptomeningeal carcinomatosis (carcinomatous meningitis). 

Central nervous system metastases was identified in 34% of patients at a median of 16 months after diagnosis of metastatic breast cancer and 6 months from the beginning of Herceptin treatment. Patients receiving Herceptin as first-line therapy for metastatic disease frequently developd brain metastases while responding to or stable on Herceptin (Cancer 2003 Jun 15;97(12):2972-7).

Trastuzumab for Breast Cancer Linked to CNS Metastases

Women with HER2-positive breast cancer who receive adjuvant trastuzumab (Herceptin, Genentech/Roche) have a significant risk for metastases in the central nervous system (CNS) as the site of first recurrence, according to a report published online March 4 in the Annals of Oncology.

"While adjuvant trastuzumab has dramatically lowered the risk of recurrence in HER2-positive breast cancer patients, clinicians should be cognizant of CNS disease as the first site of relapse and monitor survivors closely for worrisome neurologic symptoms," lead author Erin M. Olson, MD, from The Ohio State University in Columbus, told Medscape Medical News.

It has been suggested that the CNS is a sanctuary site for micrometastatic disease, either because trastuzumab does not penetrate the blood–brain barrier or because of the loss of HER2 overexpression in breast cancer cells migrating to the brain, Dr. Olson said.

In previous work, she and her colleagues found an increasing incidence of brain metastases in patients with prolonged exposure to HER2-targeted therapies. This discovery prompted her team to explore the incidence of the CNS as the first site of relapse after exposure to adjuvant trastuzumab.

They analyzed 4 phase 3 randomized controlled trials (NSABP B31, NCCTG N9831, HERA, and PACS), which involved 9020 patients in total.

Of the 4921 patients who received adjuvant trastuzumab, 125 developed CNS metastases as the site of first recurrence, for an overall incidence of 2.56% (95% confidence interval [CI], 2.07% - 3.01%). Of the 4099 patients who did not receive trastuzumab, there were 78 CNS events, for an incidence of 1.94% (95% CI, 1.54% - 2.38%).

For patients treated with trastuzumab, the ratio of CNS metastases to total recurrence events was 16.94% (95% CI, 10.85% - 24.07%). For those not treated with trastuzumab, that ratio was 8.33% (95% CI, 6.49% - 10.86%).

Additionally, the team found that the overall relative risk of developing CNS metastases as the first site of recurrence with 1 year of adjuvant trastuzumab, compared with no trastuzumab, was 1.35 (95% CI, 1.02 - 1.78; P =.038).

Dr. Olson noted that there are several limitations to this study. Among them is the fact that data were abstracted from published clinical trial results; as a result, individual patient information was not available, making it impossible to determine the timing and subsequent outcomes of the recurrences.

"Establishment of clinical risk factors associated with the development of CNS metastases as the first site of recurrence after adjuvant trastuzumab is not possible in this analysis," she explained.

Dr. Olson added that other HER2-targeted therapies, such as pertuzumab and T-DM1 (which was recently approved by the US Food and Drug Administration), might confer a similar risk.

"There is likely to be a similar risk with large antibodies that do not cross the blood–brain barrier, such as pertuzumab and T-DM1, but lapatinib has been shown to have some activity in patients with CNS disease and, therefore, the risk of CNS relapse is unknown," she said.

Study Confirms Previous Observations

Gabriel N. Hortobagyi, MD, professor of medicine at the University of Texas M.D. Anderson Cancer Center in Houston, told Medscape Medical News that this study confirms what has been known for a decade.

"Trastuzumab, being a large molecule, doesn't get into the sanctuary sites, such as the brain, and therefore is unable to affect the development of brain metastases to the same degree as it affects the development of other distant metastases," Dr. Hortobagyi explained. He was not involved in the current study.

This increased risk for CNS metastases is "an indication of success," he maintained.

"The increased risk of CNS metastases is, therefore, an indication of the success of trastuzumab in prolonging the life of patients with HER2-positive breast cancer and giving them more opportunity to develop CNS metastases. In other words, the longer you live after developing breast cancer, the greater the opportunity to develop CNS metastases," he said.

Dr. Hortobagyi agrees that the use of published aggregate data, and not individual patient reports, is a limitation. "It has limited granularity. Also, it includes several studies of somewhat different design, different chemotherapy regimens, and different follow-up times. It doesn't provide information about subsequent metastases beyond first metastases, so it is just a larger sample size to confirm earlier observations about this same phenomenon," he noted.

Some European breast cancer experts also weighed in on this study.

Evandro de Azambuja, MD, PhD, from Jules Bordet Institute in Brussels, Belgium, and Matthias Preusser, MD, from Medical University of Vienna, Austria, told Medscape Medical News by email that the study highlights "once more" the issue of developing brain metastases in HER2-positive breast cancer treated with adjuvant trastuzumab.

"HER2 overexpression is definitely a risk factor for brain metastases, and the vast majority of available systemic treatments are not able to cross the intact blood–brain barrier; therefore, even if the disease is systemically controlled, the risk of brain metastases remains," they explained.

The inclusion of only published data might not be the real problem. Other limitations include the fact that there were only a small number of published trials available, most had short follow-up periods (generally 4 years vs the most recent 8-year follow-up data), and brain metastases only as the first site were analyzed, Drs. de Azambuja and Preusser noted.

They added that it is particularly important to note that the Herceptin Adjuvant (HERA) trial group recently published data on CNS relapses in 3401 patients in the observation and 1-year trastuzumab groups (Lancet Oncol. 2013;14:244-248).

"The incidence of CNS relapse as the first site of relapse was 2% in both arms. The HERA authors also looked at a cohort of 413 patients who had died and for whom a specific questionnaire was returned, They found that 129 patients (57%) in the observation arm and 88 patients (47%) in the 1-year arm experienced CNS relapse prior to death, Drs. de Azambuja and Preusser explained.

"Therefore, reporting CNS as the first site of relapse does not fully capture the effect of CNS relapse on breast cancer outcomes. This highlights the importance of capturing CNS relapses at any time during the study, including the active phase and follow-up, in all clinical trials including HER2-positive breast cancer patients," they added.

It is not possible to say that trastuzumab increases the risk for brain metastases, "but rather that trastuzumab controls extracranial disease systemically and does not effectively cross the intact blood–brain barrier, allowing for a longer time before brain metastases develop," Drs. de Azambuja and Preusser noted.

They emphasized that HER2 overexpression itself seems to be a risk factor for CNS tumor spread, although the exact mechanism has not been established.

"New therapies focusing on the prevention of brain metastases or on increasing the permeability of the blood–brain barrier to allow systemic therapies to reach the brain should be sought," they concluded. "There is an urgent need for high-quality basic and translational research to better understand how and when tumor cells reach the brain and grow into it, and who are the patients at the highest risk of developing brain relapse."

Dr. Olson, Dr. Hortobagyi, Dr. de Azambuja, and Dr. Preusser have disclosed no relevant financial relationships.

Ann Oncol. Published online March 4, 2013

Citation: Trastuzumab for Breast Cancer Linked to CNS Metastases. Medscape. Mar 14, 2013

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