Recent improvements of systemic treatments including new cytotoxic agents and third generation aromatase inhibitors (AI) have brought to longer survival in patients with MBC. Prominently, incorporation of targeted therapies, such as trastuzumab, in HER2-positive BC has changed the natural history of this disease, prolonging survival. Consequently, many women now survive long enough to develop CNS disease. It also has emphasized local treatment modalities, such as whole brain radiation, stereotactic surgery, and tumor removal (Chargari et al. 2010; Suh 2010; Kased et al. 2009; Muacevic et al. 2004).
With BM occurring as the result of poor systemic disease control, predicting the timing of BM development may provide rationale for early intervention and treating BM considering prognostic stratification of BM. This retrospective single-center study analyzing TTBM according to BC subtype and anti-HER2 treatment trastuzumab was based on a relatively large cohort of patients with BM from BC. The distributions of HER2-positive and TNBC among BM patients from BC were higher than in those of the general proportion of BC patients, which reflects predilection to BM of HER2-positive and TNBC BCs (Slimane et al. 2004; Sanna et al. 2007; Ryberg et al. 2005; Lin et al. 2008; Heitz et al. 2009; Pestalozzi et al. 2006). In terms of TTBM from initial diagnosis of metastatic disease, median TTBM was significantly shorter in TNBC patients (2.9 months) and HER2-positive without trastruzumab treatment (5.8 months) compared patients with HR-positive/HER2-negative (17.5 months) or HER2-positive patients who received trastuzumab (13.7 months). This propensity of HER2-positive and TNBC to early BM occurrence is consistent with previous studies by Heitz et al. (2009).This result is also supported by other translational results (Sarrio et al. 2008; Lin et al. 2004; Duchnowska et al. 2009). However, they did not investigate anti-HER2 treatment effect on TTBM. In the present study, TTBM from initial primary BC was not different according to trastuzumab treatment but TTBM from initial diagnosis of distant metastases was significantly longer in HER2-positive patients with trastuzumab treatment. In multivariate analysis, both HER2-positive without trastuzumab treatment and TNBC were independently associated with earlier BM occurrence.
Prognostic model for BM from BC patients were reported and there is biologic evidence for higher propensity for BM in HER2-positive and TNBC patients (Ahn et al. 2012; Heitz et al. 2009; Sperduto et al. 2012), although routine screening of BM for high risk patients did not show definite survival benefit (Niwinska et al. 2007).While general therapeutic nihilism should be avoided, it is still important to recognize that the number of BM, the extent of the systemic disease, and also the BC subtype have to be taken into account when choosing individual treatment regimens. Finally, special emphasis will be put on established and future approaches to prevent BM. Incorporation of TTBM to prediction of prognosis in BM from BC patients may facilitate screening at most risky period, potential development of possible prophylactic strategies, and choice of treatment modalities, which are ready for prospective clinical trial.
This study is limited in that the study population is not the entire patients with BC diagnosis, but the patients who diagnosed with BM from BC, and therefore we could not evaluate the actual incidence of BM exactly. Instead, we have evaluated the TTBM from the time of first diagnosis of metastatic BC according to subtype and targeted treatment among BM patients.
Considering high cost of screening brain MRI, the prospective clinical trial selecting the patients’ population at high risk of BM who has significant benefit from screening and treating asymptomatic BM is crucial. Given that over 50% of BM in HER2-positive and TNBC occur in the first year after diagnosis of metastatic BC in this study which is compatible with previous reports (Heitz et al. 2009), it might be reasonable to confine candidates to screen asymptomatic BM to HER2-positive and TNBC population, for more risky period after initial diagnosis of metastatic disease, and screening should be considered incorporated with systemic disease control. Moreover, in these cases of BM development with well controlled extracranial systemic disease, the optimal treatment strategy is questionable whether systemic chemotherapy regimen should be changed or maintained and how local therapy should be combined with systemic treatments, especially for patients with BM as the only progression site.