Predicting the Later Occurrence of CNS Metastases in Patients with Early Breast Cancer
Predicting the Later Occurrence of CNS Metastases in Patients with Early Breast Cancer
Abstract & Commentary
By William B. Ershler, MD, INOVA Fairfax Hospital Cancer Center, Fairfax, VA; Director, Institute for Advanced Studies in Aging, Washington, DC.
Synopsis: In an effort to identify clinical characteristics of patients with early breast cancer who later develop CNS metastases, an analysis of data derived from clinical trials of the International Breast Cancer Study Group was undertaken. Although a number of risk factors were identified, none added sufficient predictive value to warrant routine screening for brain metastases.
Source: Pestalozzi BC, et al. Identifying breast cancer patients at risk for Central Nervous System (CNS) metastases in trials of the International Breast Cancer Study Group (IBCSG). Ann Oncol. 2006;17:935-944.
The occurrence of brain metastases in patients with breast cancer is ominous. Despite treatment, survival is approximately 20% at one year, although some survive longer, particularly those who present with solitary lesions, and are treated by surgical excision, with or without radiation therapy. The current report describes an effort by the International Breast Cancer Study Group to identify clinical factors that would indicate an increased risk of developing CNS metastases. They evaluated data from 9,524 women with early breast cancer (42% node-negative) who were randomized in their group trials between 1978 and 1999, and treated without anthracyclines, taxanes, or trastuzumab. Patients were identified whose site of first event was CNS, and also those who had CNS event at any time.
At a median follow-up of 13 years, 46.2% of all patients were alive without recurrence; 53.8% (5122 of 9524) experienced either disease recurrence at known sites (n = 3937), contralateral breast cancer (n = 384), failure at an unknown site (n = 39), a non breast cancer second malignancy (n = 389) or death without recurrence (n = 376). Overall, CNS was a component of first recurrence in 1.3% of patients (126 of 9524) and of these, 55 patients experienced their CNS recurrence within 2 months of discovering recurrence at other sites.
Factors associated with CNS recurrence included: node-positive disease (10 yr = 2.2% for > 3 nodes +), estrogen receptor negative (2.3%), tumor size > 2 cm (1.7%), tumor grade 3 (2%), younger than 35 years old (2.2%), HER2 positive (2.7%), and estrogen receptor-negative and node positive (2.6%). The risk of subsequent CNS recurrence was elevated in patients experiencing lung metastases (10 yr = 16.4%).
Thus, certain clinical factors were associated with increased risk of CNS metastases, but the increased risk was of insufficient magnitude to identify a population for routine screening for occult CNS metastases.
Commentary
The goal of this well constructed analysis was to provide for clinicians a profile of characteristics that might predict the development of CNS involvement as the initial site of recurrent disease in breast cancer patients. This, of course, would be useful, because only modest effects result from current therapeutic approaches. Whole brain radiation with local boost have been shown to improve survival for those with solitary metastases compared with whole brain radiation alone and to improve local control for those with up to 3 or 4 lesions.1 The only chance for prolonged survival in this setting is surgery, which is generally restricted to those with solitary metastatic lesions without active disease elsewhere.2 However, few are eligible for this, primarily because recurrence is frequently associated with active disease elsewhere or the CNS lesion is not solitary. Theoretically, an active screening program for high risk patients might identify earlier CNS involvement and identify patients who might benefit from surgery.
In this series of nearly 10,000 patients treated on adjuvant chemotherapy protocols, the 10-year CNS recurrence rate was 5.2%. This is similar to another population-based analysis (5.1%), but significantly lower than what has been reported for patients who presented with advanced disease and were treated with either taxane or trastuzumab. For example, in one series, CNS metastasis was observed in 34% of patients treated with trastuzumab.3 In the current series HER-2 status was available for approximately 40% of the cases and it was clear from the data presented that these individuals, treated in the adjuvant setting at a time before trastuzumab was available, also had increased risk of CNS recurrence. This sets well with the current understanding of increased tumor aggressiveness when HER-2 is over-expressed.
Thus, the current analysis did not identify any patient group with sufficiently high risk to warrant routine screening. Furthermore, it should be noted that it has yet to be demonstrated that earlier recognition of CNS disease prolongs survival. In fact, in one series of 155 patients with metastatic disease screened for occult CNS disease,4 lesions were discovered in 23 (14.8%) and, as expected, their survival was less than those who did not have brain metastases. It remains unclear whether earlier recognition afforded any advantage for these patients.
References
1. Tsao MN, et al. The American Society for Therapeutic Radiology and Oncology (ASTRO) evidence-based review of the role of radiosurgery for malignant glioma. Int J Radiat Oncol Biol Phys. 2005;63:47-55.
2. Patchell RA, et al. A randomized trial of surgery in the treatment of single metastases to the brain. N Engl J Med. 1990;322:494-500.
3. Bendell JC, et al. Central nervous system metastases in women who receive trastuzumab-based therapy for metastatic breast carcinoma. Cancer. 2003;97:2972-2977.
4. Miller KD, et al. Occult central nervous system involvement in patients with metastatic breast cancer: prevalence, predictive factors and impact on overall survival. Ann Oncol. 2003;14:1072-1077.
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