ArticlesCNS relapses in patients with HER2-positive early breast cancer who have and have not received adjuvant trastuzumab: a retrospective substudy of the HERA trial (BIG 1-01)
Introduction
The HERA trial (BIG 1-01) is a large randomised phase 3 study comparing treatment with adjuvant trastuzumab after standard adjuvant chemotherapy for 1 year or 2 years with only observation in patients with HER2-positive early breast cancer.1, 2, 3, 4 On the basis of the results of HERA and several other trials, including NSABP B-31,5 NCCTG N9831,5 and BCIRG 006,6 1 year of adjuvant trastuzumab in combination with, or sequential to, chemotherapy was established as the standard treatment for patients with HER2-positive early breast cancer.
According to epidemiological and retrospective studies,7, 8, 9 CNS metastases occur in 5–15% of patients with breast cancer. Conversely, a large autopsy study10 suggested that up to 30% of these patients have CNS metastases. CNS metastases are known to occur more frequently in patients with at least four positive nodes, tumours larger than 5 cm, and high-grade tumours, and in those with oestrogen receptor (ER)-negative disease.9 The proportion of patients with HER2-positive advanced breast cancer who have CNS metastases has been reported to be as high as 20–50%.11, 12, 13, 14 The reasons for the high risk of CNS relapses in HER2-positive breast cancer is the subject of continuing debate, with suggestions of biology-linked tropism or poor CNS penetration of trastuzumab through the intact blood–brain barrier, or both, leading to a sanctuary site for CNS disease despite effective therapy against non-CNS disease.15
Several randomised trials of adjuvant trastuzumab have identified CNS as the first site of relapse: in the NSABP B-31 trial,5 CNS metastases were recorded in 3·2% of patients receiving trastuzumab and 4·0% of those not given trastuzumab; in the NCCTG N9831 trial,5 1·49% and 0·5% had CNS metastases; and in the HERA trial,3 1·53% and 1·30% had CNS metastases. In the most recent update of HERA (4-year median follow-up),1 the frequency of CNS metastases as first recurrence site had increased to 2·17% in the group given trastuzumab for 1 year and 1·88% in the observation group.
A meta-analysis16 of these trials showed that the risk of developing brain metastases (ie, CNS metastases) was significantly higher for patients given trastuzumab than for those not given trastuzumab (relative risk [RR] 1·57, 95% CI 1·03–2·37; absolute difference 0·62%). Some could interpret this result as evidence that CNS relapse is a side-effect of trastuzumab. However, the result was based on CNS relapse as first disease-free survival (DFS) event and CNS relapses as second or subsequent site of relapse were not considered.
Trastuzumab is a large molecule that does not cross the intact blood–brain barrier.15 The substantial reduction in risk of non-CNS relapses associated with trastuzumab could explain the increased likelihood that CNS relapses (which would have emerged subsequently anyway during the course of follow-up) are identified as first site of relapse in patients given the drug. We decided to further investigate the frequency and course of CNS relapses in patients in the HERA trial, comparing patients with HER2-positive early breast cancer given 1 year of adjuvant trastuzumab and patients who were only observed.
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Patients and procedures
The HERA study design, eligibility criteria, randomisation, treatment schedule, and follow-up have been reported previously.3, 4 Briefly, between Dec 7, 2001, and June 20, 2005, patients with HER2-positive early breast cancer were randomly assigned to receive 1 year or 2 years of trastuzumab or to observation.1, 2, 3, 4 The present analysis includes only data for 3401 patients assigned to receive 1 year of trastuzumab (n=1703) or observation (n=1698). We did not include data from patients
Results
In all patients randomly assigned to observation or 1 year of trastuzumab, more patients who had CNS relapse as first DFS event had four or more positive lymph nodes, large tumours, and ER-negative and progesterone-receptor-negative tumours than did patients who had no DFS event (table 1). Of 816 patients with a first DFS event, 69 (8%) had a CNS relapse as first site of recurrence (table 2). The cumulative incidence of CNS relapses as first DFS event did not differ between patients given 1
Discussion
We have shown that the risk of a first recurrence in the CNS is low in patients with HER2-positive early breast cancer and is not significantly affected by the use of adjuvant trastuzumab. By contrast, adjuvant trastuzumab was associated with fewer CNS relapses at any time than was observation in patients who had died for whom we had additional data (panel). Known risk factors for CNS relapse as first DFS event have been confirmed in our study. The proportion of patients who had CNS metastases
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