Clinical Investigation
The Effect of Early Detection of Occult Brain Metastases in HER2-Positive Breast Cancer Patients on Survival and Cause of Death

Presented as a poster discussion at the 43th American Society of Clinical Oncology Annual Meeting, June 1–5, 2007, Chicago, IL, and published in abstract form [Effect of early detection of occult brain metastases in HER2-positive breast cancer patients on survival. J Clin Oncol 2007;25(Suppl):35s.]
https://doi.org/10.1016/j.ijrobp.2009.06.030Get rights and content

Purpose

The aim of the study is to evaluate disease-free survival, survival from the detection of brain metastases, overall survival, and cause of death in patients with occult brain metastases (Group I) vs. patients with symptomatic brain metastases (Group II).

Methods and Materials

In 80 HER2-positive breast cancer patients, treated with trastuzumab and cytostatic agents for metastatic disease, magnetic resonance imaging screening of the brain was performed, and in 29 patients (36%) occult brain metastasis was detected (Group I). Whole-brain radiotherapy was delivered to Group I. This first group was compared with 52 patients who had symptomatic brain metastases (Group II) and was treated the same way, at the same clinic, during the same time period.

Results

Median disease-free survival was 17 months in Group I and 19.9 months in Group II (p = 0.58). The median time interval between the dissemination of the disease and the detection of occult or symptomatic brain metastases was 9 and 15 months, respectively (p = 0.11). When the brain metastases were detected, the median survival was 9 and 8.78 months, respectively (p = 0.80). The median overall survival was 53 and 51 months, respectively (p = 0.94). In the group with occult brain metastases (Group I) 16% of patients died because of progression within the brain. In the group with symptomatic brain metastases (Group II) the rate of cerebral death was 48% (p = 0.009).

Conclusions

Whole-brain radiotherapy of occult brain metastases in HER2-positive breast cancer patients with visceral dissemination produces a three-fold decrease in cerebral deaths but does not prolong survival.

Introduction

HER2-positive breast carcinoma is a more aggressive subtype of breast cancer 1, 2, 3, leading to a higher risk of dissemination to the central nervous system 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18. Systemic chemotherapy and targeted therapy have improved response rates and extended survival rates. However, the high efficacy of systemic therapy in extracranial disease does not apply to the efficacy in the case of brain metastases, because of impaired penetration of some drugs through the blood–brain barrier 4, 18. Nowadays, because of prolonged survival, some patients may remain alive long enough to have brain metastases develop. Therefore the growing number of patients with central nervous system metastases has become an important clinical problem. The role of magnetic resonance imaging (MRI) screening to detect an early asymptomatic brain metastasis in HER2-positive patients with disseminated disease is widely discussed. Prevention of severe neurologic symptoms or even prolonged survival is expected. Prophylactic cranial irradiation in patients with complete response to trastuzumab or in HER2-positive breast cancer patients after completion of adjuvant therapy is also discussed 1, 3, 5, 18. According to standard protocols, routine brain screening in asymptomatic patients with disseminated disease is not performed because, up to now, no convincing data to support the benefit related to early diagnosis and treatment of brain metastases have been available 18, 19.

The question arises as to whether early detection of brain metastases and whole-brain radiotherapy (WBRT) could improve the outcomes in patients with occult brain metastases, either by delaying or preventing neurologic symptoms or by prolonging survival.

The aim of this study is to assess the risk factors of occult brain metastases in HER2-positive breast cancer patients, as well as to analyze disease-free survival (DFS), survival from the detection of brain metastases, overall survival, and cause of death in patients with occult brain metastases (Group I). Those results will be compared with the results of patients with symptomatic brain metastases (Group II).

Section snippets

Patients and study design

The study was started after approval was obtained from the Bio-Ethical Committee of the Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland. From December 2004 until June 2006, 80 HER2-positive breast cancer patients with distant metastases and/or locoregional failure were enrolled in the study to undergo MRI screening of the brain during the asymptomatic period (screening cohort). Eligible patients either had recently been detected with dissemination of the

Incidence of occult brain metastases

During the 20-month follow-up, occult brain metastases were found in 29 of 80 patients (36%). The median time between recurrence (distant and/or locoregional) and the diagnosis of occult brain metastases was 9 months (range, 0–76 months). A single brain metastasis occurred in 10 patients (34%), and multiple lesions occurred in 19 patients (66%). The tumor diameter ranged from 2 to 50 mm, usually being 5 to 10 mm. In the majority of cases edema did not accompany the metastases, and in only a few

Epidemiology

Symptomatic brain metastases are documented in 6% to 16% of patients 1, 4, 18, 20, 21, although autopsy results suggest that a 18% to 30% rate seems more realistic 22, 23, 24. In a group of patients with HER2 overexpression, the incidence of symptomatic brain metastases is even higher, reaching 24% to 48% 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16. In our series occult brain metastases were found in 36% of patients. There are not enough data published on occult brain metastases in

Conclusions

In HER2-positive breast cancer patients with visceral and brain metastases, WBRT performed during the asymptomatic period had no influence on survival, even though it decreased the risk of cerebral death. Of important note, the results of the study showed a failure in the treatment of extracranial disease rather than brain metastases. We have shown, for the first time, that brain metastases detected and irradiated before the occurrence of clinical symptoms do not have to lead to death.

References (30)

  • R.K. Lai et al.

    The incidence of brain metastases in HER2/neu+ stage IV breast cancer patients

    Proc Am Soc Clin Oncol

    (2001)
  • A.M. Wardley et al.

    High incidence of brain metastases in patients treated with trastuzumab for metastatic breast cancer at a large cancer center

    Proc Am Soc Clin Oncol

    (2002)
  • R. Weitzen et al.

    High incidence of brain metastasis (BM) in patients on trastuzumab (H) for advanced breast cancer

    Proc Am Soc Clin Oncol

    (2002)
  • A.J. Clayton et al.

    Incidence of cerebral metastases in patients treated with trastuzumab for metastatic breast cancer

    Br J Cancer

    (2004)
  • D.G. Hicks et al.

    Breast cancer with brain metastases are more likely to be estrogen receptor negative, express the basal cytokeratin CK5/6 and overexpress HER2 or EGFR

    Am J Surg Pathol

    (2006)
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