|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
Journal of Clinical Oncology, Vol 23, No 9 (March 20), 2005: pp. 2114-2116 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.05.249
Survival After Brain Metastases From Breast Cancer in the Trastuzumab EraMassachusetts General Hospital, Boston, MA To the Editor: In a recent study, Andre et al1 reported improved survival for breast cancer patients presenting with synchronous metastases over time (1987 to 2000). They suggested that improved survival was related to treatment. Improved survival seemed to be limited to patients with hormone receptor–positive tumors, but as the authors noted, most patients were not treated with trastuzumab. Recent reports of patients with metastatic breast cancer treated with trastuzumab have documented an incidence of CNS metastases of 25% to 34%.2-5 To examine the effect of trastuzumab on patients with brain metastases from breast cancer, we searched for women at the Massachusetts General Hospital who had a history of primary breast cancer that developed brain metastases between June 1998 and May 2003. After receiving approval from our institutional review board, we retrospectively identified 108 women from hospital records with intraparenchymal brain metastases from a primary breast cancer. Tumors were classified as HER2 overexpressing if the primary or metastatic lesion had been scored as either strong overexpression (3+) for HER2 by immunohistochemistry (IHC) or if the tumor showed HER2/neu gene amplification by fluorescence in situ hybridization (FISH). Tumors were classified as HER2 nonoverexpressing if they had been scored as having either weak expression (1+) for HER2 by IHC or if they did not show HER2/neu gene amplification by FISH. For tumors that lacked prior HER2 analysis, HER2 IHC was performed on paraffin-embedded blocks with a rabbit polyclonal antibody to HER2 (Dako Corp, Carpeinteria, CA). For all tumors that were scored as having moderate (2+) HER2 expression by IHC, FISH analysis was performed with the HER2 DNA Probe Kit (Vysis Inc, Downers Grove, IL). Of the 108 patients, 47 were classified as having tumors with HER2 overexpression, and 48, without HER2 overexpression (Table 1) . Thirteen patients could not be classified for HER2 expression because the tumor blocks were unavailable or because FISH was unsuccessful. For patients with HER2-overexpressing breast cancer, there was no statistically significant difference in (1) the median age at the time the primary breast cancer was diagnosed, (2) the time to develop brain metastases, (3) the number of brain metastases, or (4) the type of therapy for the brain metastases (Table 1). However, patients with HER2-overexpressing breast cancer had a significantly longer survival after developing brain metastases compared with patients with tumors that did not overexpress HER2 (22.4 v 9.4 months from date of brain metastasis, respectively; P = .0002 by log-rank test).
The survival advantage for patients with brain metastases from tumors that overexpress HER2 does not seem to be due to an intrinsic biologic advantage of HER2 overexpression. Patients with HER2-overexpressing tumors who did not receive trastuzumab had survival similar to that of patients with tumors that did not overexpress HER2 (Figure 1). HER2 overexpression, however, was necessary to derive benefit from trastuzumab. For patients with tumors lacking HER2 overexpression, survival was similar whether or not they received trastuzumab (data not shown).
Interestingly, the survival advantage did not correlate with better control of the brain metastases. Follow-up magnetic resonance imaging studies (n = 55) demonstrated that one half of patients showed disease progression in the brain within 8 months after the diagnosis of brain metastases, regardless of the HER2 status. Instead, the survival advantage may result from better control of extracranial systemic disease in patients with HER2-overexpressing tumors who received trastuzumab.5 This interpretation is consistent with a randomized controlled trial that concluded that aggressive therapy for a single brain metastasis (from a variety of primary cancers) improves survival only if extracranial disease is controlled.6 These results suggest that the conclusions from the study by Andre et al1 extend to patients with brain metastases when they receive effective systemic therapy (trastuzumab). Furthermore, the results have important clinical implications for the treatment of patients with HER2-overexpressing breast cancer. Since survival following brain metastases is relatively long if these patients received trastuzumab, their brain metastases should be treated aggressively, but in a manner that minimizes late effects. Specifically, whole-brain radiation therapy should be delivered in relatively small daily fractions (such as 2 to 2.5 Gy/d). When patients are receiving trastuzumab and develop metastases only in the CNS, trastuzumab should be continued in order to control extracranial disease. In these patients, failure in the CNS does not represent resistance of the tumor to trastuzumab, but instead likely reflects the inability of trastuzumab to cross the blood-brain barrier. Since as many as a third of patients with metastatic breast cancer develop brain metastsases, prophylactic treatment of the brain should be considered in patients with HER2-overexpressing breast cancer within the context of a clinical trial. Prophylactic cranial irradiation may benefit patients treated with trastuzumab for metastatic breast cancer that overexpresses HER2. In the future, another approach to prophylactic therapy and treatment of brain metastases that overexpress HER2 may include drugs that target HER2 and cross the blood-brain barrier.7 Authors' Disclosures of Potential Conflicts of Interest The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Consultant: Fred H. Hochberg, Schering-Plough, Abbott Laboratories. Other Remuneration: Fred H. Hochberg, Sigma Tan. For a detailed description of these categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section of Information for Contributors found in the front of every issue.
Acknowledgment This study was supported by the Leaf Fund and a Young Investigator Award from the American Society of Clinical Oncology (D.G.K.), which was funded by Aventis. REFERENCES
1. Andre F, Slimane K, Bachelot T, et al: Breast cancer with synchronous metastases: Trends in survival during a 14-year period. J Clin Oncol 22:3302-3308, 2004 2. Bendell JC, Domchek SM, Burstein HJ, et al: Central nervous system metastases in women who receive trastuzumab-based therapy for metastatic breast carcinoma. Cancer 97:2972-2977, 2003[CrossRef][Medline] 3. Shmueli E, Wigler N, Inbar M: Central nervous system progression among patients with metastatic breast cancer responding to trastuzumab treatment. Eur J Cancer 40:379-382, 2004 4. Clayton AJ, Danson S, Jolly S, et al: Incidence of cerebral metastases in patients treated with trastuzumab fro metastatic breast cancer. Br J Cancer 91:639-643, 2004[Medline] 5. Lower EE, Drosick DR, Blau R, et al: Increased rate of brain metastasis with trastuzumab therapy not associated with impaired survival. Clin Breast Cancer 4:114-119, 2003[Medline] 6. Noordijk EM, Vecht CJ, Haaxma-Reiche H, et al: The choice of treatment of a single brain metastasis should be based on extra-cranial tumor activity and age. Int J Radiat Oncol Biol Phys 29:711-717, 1994[Medline]
7. Kirsch DG, Hochberg FH: Targeting HER2 in brain metastases from breast cancer. Clin Cancer Res 9:5435-5436, 2003 This article has been cited by other articles:
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
