Breast Cancers With Brain Metastases are More Likely to be Estrogen Receptor Negative, Express the Basal Cytokeratin CK5/6, and Overexpress HER2 or EGFR

Abstract

Brain metastases (BM) from breast cancer are associated with significant morbidity and mortality. In the current study, we have examined a cohort of breast cancer patients who went on to develop BM for clinical-pathologic features and predictive markers that identify this high-risk subgroup of patients at the time of diagnosis. The primary tumors from 55 patients who developed BM were used to construct a tissue microarray. The clinical and pathologic features were recorded and the tissue microarray was stained for estrogen receptor, human epidermal growth factor receptor 2, cytokeratin 5/6, and epidermal growth factor receptor by immunohistochemistry. This cohort of patients was compared against a group of 254 patients who remain free of metastases (67 mo mean follow-up), and another cohort of 40 patients who developed mixed visceral and bone metastatic disease without brain recurrence over a similar period of time. Breast cancer patients who went on to develop BM were more likely to be <50 years old (P<0.001), and the primary tumors were more likely to be estrogen receptor negative (P<0.001) and high grade (P=0.002). The primary tumors were also more likely to express cytokeratin 5/6 (P<0.001) and epidermal growth factor receptor (P=0.001), and to overexpress human epidermal growth factor receptor 2 (P=0.001). The data presented above suggest a profile for breast cancer patients at increased risk for developing BM. Predictive factors to help identify patients with metastatic breast cancer who are at an increased risk for developing central nervous system recurrence might allow for screening of this population for early detection and treatment or for the development of targeted strategies for prevention.

Mystery of the brain metastatic disease in breast cancer patients: improved patient stratification, disease prediction and targeted prevention on the horizon?

“…The cumulative incidence of BM has been demonstrated to be higher for the patients having more than four positive lymph nodes (8.5% at 10 years follow-up, P < 0.01), tumour grade 3 (7.8% at 10 years follow-up, P < 0.01) and the tumour size more than 2 cm (6.8% at 10 years follow-up, P < 0.01). The higher BC tumour grade was identified as strongly associated with BM risk (P = 0.002) in an independent study [13]. Significantly more BC patients with BM than without BM had tumour of higher histological grade (grade 3, 78.9 vs. 30.2%; P = 0.001) as confirmed by the recently performed issue-dedicated study [15].…”

“…Another study with 2685 metastatic BC patients and multivariate analysis performed revealed the ER negativity as an independent predictor of the increased BM risk compared to ERpositive tumours (HR = 2.8, 95% CI 2.1-3.7, P < 0.001) [10]; thereby, the BM recurrence were more common in patients with HER2-positive tumours (P = 0.04). BC patients that suffered from BM were more likely to have ER-negative (P < 0.001) and HER2 overexpressing (P = 0.001) tumours as demonstrated by another independent study [13].…”

“…Recorded cumulative incidence of BM was significantly higher for BC patients younger than 50 years (20.8%) compared to the older ones (9.7%) by observing follow-up during 5 years [11]. A series of independent studies which differed from each other by experimental design and patient subgroups involved, have, nevertheless, confirmed these main findings [12,13], namely:…”

Basal-like and triple-negative breast cancers: a critical review with an emphasis on the implications for pathologists and oncologists

“…114 However, when compared with either ERÀ non-basal-like cancers 72 or grade-matched non-basal-like cancers, 42 carcinomas with a basal-like phenotype are not associated with a poorer outcome in some studies, whereas a more adverse prognosis is observed in others. 19,116 The pattern of metastatic spread of tumors with a basal-like phenotype seems to be different from that of non-basal-like cancers: they are reported to less frequently disseminate to axillary nodes and bones 42,117 and to favor a hematogenous spread, 42,[117][118][119] with a peculiar proclivity to develop metastatic deposits in the brain and lungs. 120 It should be noted that patients with triple-negative and basal-like cancers tend to develop adverse events and die due to disease within the first 5-8 years after diagnosis.…”

Antidepressant use and risk of central nervous system metastasis

“…Although knowledge regarding modifiable risk factors is scarce, several nonmodifiable risk factors are known to influence the cumulative incidence of brain metastasis. Brain metastasis are more common in younger cancer patients than older cancer patients in breast cancer and melanoma [8,9,153,185,[187][188][189][190][191][192][193][194]. The risk of brain metastasis appears to increase until 40 to 49 years of age and then decline thereafter [131].…”