Risk factors for the development of brain metastases in patients with HER2-positive breast cancer

Abstract

BackgroundPatients with metastatic human epidermal growth factor receptor 2-positive breast cancer (HER2+ BC) frequently experience brain metastases (BM). We aimed to define risk factors for the development of BM in patients with HER2+ BC and to report on their outcome.MethodsThis is a retrospective analysis of patients diagnosed with HER2+ BC between January 2000 and December 2014 at Institut Jules Bordet, Belgium. Statistical analyses were conducted with SAS V.9.4 using Kaplan-Meier method and Cox regression analyses.ResultsA total of 483 patients were included of whom 108 (22.4%) developed metastases and 52 (10.8%) BM. Among 96 metastatic patients without BM at diagnosis, 40 (41.7%) developed BM in the course of their disease. In multivariate analysis, risk factors for the development of BM were age ≤40 years (HR 2.10, 95 % CI 1.02 to 4.36), tumour size >2 cm (HR 4.94, 95% CI 1.69 to 14.47), nodal involvement (HR 3.48, 95% CI 1.47 to 8.25), absence or late start (≥6 months after initial diagnosis) of adjuvant anti-HER2 treatment (HR 3.79, 95% CI 1.52 to 9.43 or HR 2.65, 95% CI 1.03 to 6.82) and the development of lung metastases as first site of relapse (HR 6.97, 95% CI 3.41 to 14.24). Twenty-two patients with HER2+ BC and BM sent to our institute for further treatment were included in the outcome analysis. Asymptomatic patients at the time of BM diagnosis showed a better overall survival than symptomatic patients (HR 0.49, 95% CI 0.25 to 0.94).ConclusionA considerable number of patients with metastatic HER2+ BC will develop BM. Screening of patients with risk factors for BM might lead to early detection and better outcome. However, randomised controlled trials examining the use of MRI as a screening method for BM in patients with metastatic BC are warranted before such an approach can be recommended.

Risk Factors for Brain Metastases in Patients with Renal Cell Carcinoma

“…The study conducted by Hung et al [14] revealed that patients ≤ 35 years tended to develop cerebral lesions in patients with breast cancer. Maurer et al [15] showed that age ≤ 40 years was a risk factor for BM in patients with HER2-positive breast cancer. Our results demonstrated that younger patients were prone to developing brain metastases, which was similar to previous speculations.…”

“…Schovanek et al [16] suggested that 4.5 cm was the optimal cut-off primary tumor size which can predict development of any metastases from pheochromocytoma/paraganglioma. Maurer et al [15] identified tumor size > 2 cm as a risk factor for the development of BM in patients with HER2-positive breast cancer. Sun et al [7] revealed that white/other race, clear cell histology, sarcomatoid differentiation, T2-4 disease, tumor dimension > 10 cm, and N+ disease were risk factors of BM development at RCC diagnosis.…”

Risk factors for breast cancer brain metastases: a systematic review

“…Unlike the general BC population, the effect of age on the risk for BCBM in TNBC and HER2-positive patients was not as prominent. Five studies reported a statistically significant multivariable association between young age and risk for BCBM with effect estimates ranging between 1.66 -2.7 [17,25,26,44,80], whilst no significant association was found in the rest of the studies considering solely HER2-positive patients, likely reflecting the small sample size used [20, 23-25, 61, 81]. Similarly, in the subset of studies involving TNBC patients, age was not found to impact BCBM [24,39,71].…”

“…High primary tumor histological grade (G3 vs. G1-2) was recurrently associated with BCBM progression, with twelve [19,28,29,36,38,51,52,57,59,70,78,79] of the 19 studies examined [12, 16, 19, 28, 29, 33, 36, 38, 40, 50-53, 57, 59, 70, 72, 78, 79], reporting a statistically significant univariate association. On multivariate analysis, a significant positive association between Grade 2 [26,80] 5 NR, p < 0.05 [17]; <50 years, HR: 2.7, p = 0.0048 [25]; ≤50 years, HR: 1.92 p = 0.04 [26]; Young age OR: 1.66 p = 0.014 [44]; ≤40 years, p = 0.045 [80] Hormone receptor status 7 [20,26,27,44,61,66,80] 3 [20,44,66] 2 Negative, OR: 1.75 p = 0.033 [44]; Negative, RR: 3.41 p = 0.01 [ [17,23,24,44,47,61] 2 [47,61] 3 OR:1.61 p = 0.025 [80]; Late (≥6 months after BC diagnosis), HR: 2.65, p = 0.043, No, HR:3.79, p = 0.0042 [44]; ≥2 line OR: 3.43 p = 0.003 [61] HR -Hazard Ratio; OR -Odds Ratio; RR -Relative risk; NR -Not Reported.…”

“…In studies considering solely HER2-positive patients, multivariate analysis revealed HR-negativity to associate with a statistically significant higher risk of brain as the first relapse site (effect estimate range: 1.75 -3.41) [44,66]; however the trend did not reach statistical significance when ER/PR statuses were compared between HER2-positive BM and non-BM cases overall [23, 26,27,44,80,81]. HER2 protein expression in primary BC tumors was also found to associate with higher risk for BCBM [19,35,38,52,53,67,73,75,78] with seven studies reporting statistically significant multivariable associations (effect estimate range: 1.89 -7.039) [18,24,40,51,53,57,78].…”