About 10% to 30% of patients with metastatic breast cancer develop brain metastases (BM) 1 . Several reports suggest that the risk of developing BM is higher (25% to 40%] in patients receiving trastuzumab-based therapy for HER2-overexpressing metastatic breast cancer 2 3 4 5 6 7 8 9 . Whole-brain radiotherapy (WBRT] is considered the standard treatment for most patients, particularly those with extensive intra-cranial disease, providing symptom relief and prolonging both median and overall survival (1,10-12). Despite the use of WBRT, the prognosis of patients with BM remains poor, with a median survival time of approximately 5 months 1 10 11 12 13 14 . Recent studies have examined the influence of patient characteristics on survival in this setting and have attempted to identify subgroups of patients with substantially different outcomes in order to tailor therapy and to rationalize the design, stratification and interpretation of clinical trials 13 14 15 16 17 18 19 . The Radiation Therapy Oncology Group (RTOG] recursive partitioning analysis (RPA) classification based on clinical factors (Karnofsky performance status, age, and control of extracerebral disease) is a major prognostic indicator for patients with brain metastases 13 . Several reports suggest that trastuzumab-treated HER2-positive breast cancer patients with BM fare better than HER2-negative breast cancer patients and patients with HER2-positive tumors who do not receive trastuzumab 20 21 22 23 24 25 26 . The prognostic significance of HER-2 overexpression and trastuzumab-based therapy has not been analyzed in the previously published prognostic scores of patients with brain metastases. The aim of this study was to confirm, in a cohort of patients with BM from breast carcinoma, the beneficial effect of trastuzumab in patients with HER2-positive disease, and to analyze the cause of death.

Because several subgroups of metastatic breast cancer patients are at a high risk of developing BM 5 9 and because systemic therapy, particularly trastuzumab, has limited efficacy for preventing or controlling intracranial metastases, BM are becoming a major issue in this setting, being associated with poor survival and quality of life 28 29 . Risk factors for the development of CNS metastases from breast cancer include patient characteristics, such as young age and African-American ethnicity, and biological features of the tumor, including ER-negativity, HER2-positivity, high tumor grade, and BRCA1 phenotype 1 7 30 31 32 . Breast cancer patients with brain metastases form a heterogeneous population with respect to their prognosis 14 20 21 22 23 24 25 26 . Identification of patient subgroups with substantially different outcomes is therefore necessary to tailor therapy and to help with the design, stratification and interpretation of future clinical trials. The RTOG RPA classification is currently recognized as a major prognostic indicator in patients with brain metastases. It comprises three prognostic classes based on Karnofsky performance status, age, and control of extracerebral disease 13 . In this classification, the best survival (RPA Class I), with a median of 7.1 months, was observed in patients younger than 65 years of age with a KPS of at least 70, a controlled primary tumor, and metastases restricted to the brain. The worst survival (RPA Class III), with a median of 2.3 months, was seen in patients with a KPS below 70. The remaining patients (RPA Class II) had a median survival of 4.2 months. Several other prognostic scores for patients with brain metastases from different primaries 14 15 16 17 18 19 were subsequently developed, but none of them include molecular features or breast cancer-specific parameters such as tumor HER-2 overexpression, nor specific treatments.

Several groups have published retrospective studies describing improved survival from time of BM diagnosis in BM patients with HER2-positive BC treated with trastuzumab, compared with HER2-negative breast cancers 20 21 22 23 24 25 26 . In a retrospective study including 56 patients with HER2-positive BC who developed BM, Nam and colleagues reported a median OS of 13 months in 21 patients who received trastuzumab after diagnosis of mCNS disease compared with 4 months in those (n = 35) who did not receive trastuzumab after diagnosis and 3 months in 70 BM patients with HER2-negative tumors (p = 0.0011) 26 . Bartsch and colleagues also analyzed the effect of the continuation of trastuzumab after diagnosis of BM for 17 patients, in comparison with a cohort of 36 pts with HER2 overexpressing tumors not treated with trastuzumab after WBRT 20 . In this report, KPS and trastuzumab were associated with better overall survival, with a trend towards longer time to in-brain progression. Our results confirm the fact that trastuzumab-treated HER2-positive breast cancer patients with BM fare better than HER2-negative breast cancer patients and patients with HER2-positive tumors who do not receive trastuzumab 20 21 22 23 24 25 26 . In agreement with three previous reports, this survival advantage for patients with brain metastases from tumors that overexpress HER2 does not seem to be due to an intrinsic biologic advantage of HER2 overexpression, as patients with HER2-overexpressing tumors who did not receive trastuzumab had survival similar to that of patients with tumors that did not overexpress HER2 23 26 33 . In our experience, about 60% of HER-2 positive patients treated with trastuzumab who died apparently succumbed from CNS progression. Similarly, in a retrospective series of 122 patients treated with trastuzumab between 1998 and 2000 at Dana-Farber/Partners Cancer Care, about 50% of the 21 patients with brain metastases who died apparently succumbed from CNS progression, despite stable or responsive non-CNS disease 34 . These results suggest that HER2 targeting may improve brain metastasis outcomes through durable control of systemic extracranial disease in HER2-positive breast cancer patients 35 . However, one should keep in mind that the determination of the cause of death is difficult in this context. As systemic therapies improve, there is concern that the incidence of symptomatic brain metastases will increase, and that control of CNS disease will become a more vital component of overall disease control and quality of life. Althought the clinical activity of trastuzumab on brain metastases remains debated, trastuzumab may cross the blood-brain barrier when its permeability is increased, as it occurs during WBRT 36 . Preclinical results also found that trastuzumab may act synergistically with radiation in a HER2 level-dependent manner 37 , encouraging further assessment in combination with WBRT. Chargari and colleagues reported preliminary results of WBRT with concurrent trastuzumab for treatment of BM in 31 BC patients 38 . After WBRT, radiologic responses were observed in 23 patients (74.2%), including 6 (19.4%) with a complete radiologic response and 17 (54.8%) with a partial radiologic response. No Grade 2 or greater acute toxicity was observed. The median survival time from the start of WBRT was 18 months [range, 2-65] and the median interval to brain progression was 10.5 months [range, 2-27]. By dual inhibition of HER1 and HER2, lapatinib also demonstrated a modest efficacy in HER2-positive breast cancer patients with brain metastases 39 . However, Lin et al. found that up to 20% patients with CNS progression after cranial radiation receiving lapatinib and capecitabine experience an objective response 40 . Lapatinib is currently under investigation in combination with WBRT in an ongoing, phase I trial 41 . A phase II study is also currently assessing the efficacy and safety of concurrent WBRT and capecitabine followed by combination capecitabine and sunitinib for treatment of brain metastases from breast cancer 42 . Concurrent chemoradiation is also currently being investigated with the aim of improving the control rate of both cerebral and systemic disease 39 43 . Regarding WBRT fractionation, several trials have examined the influence of the dose, timing and fractionation of WBRT, without identifying a clearly superior schedule 11 . The most widely used WBRT regimen delivers 30 Gy in ten 3-Gy fractions, but this may be inadequate for long-term tumor control. Li et al. recently examined the outcomes of 208 patients who received WBRT as 10 daily 3-Gy fractions in the control arm of the PCI-P120-9801 phase III trial of motexafin gadolinium 44 . Neurocognitive function (NCF) and survival were compared in 135 patients assessable at 2 months with tumor shrinkage below (poor responders) and above (good responders) the population median (45%) on MRI. Good responders survived significantly longer than poor responders (median 300 ± 26 vs 240 ± 19 days; p = .03), and had a longer median time before NCF deterioration, supporting the use of techniques to maximize intracranial control, particularly for patients with HER-2-overexpressing tumors treated with trastuzumab. In our experience, BM patients with HER-2 overexpressing tumors treated with trastuzumab can expect a median overall survival time of about 20 months and a 1-year survival rate of about 60%. This subgroup of patients may therefore have a higher risk of experiencing late radiation-related toxicity such as neurocognitive dysfunction, and might benefit from longer-course WBRT with lower doses per fraction 45 . Further studies of more aggressive local therapy with different dose and fractionation schedules, in a manner that could minimize late effects, could probably be more efficient for this subgroup of patients supposed to have longest median survival.

The combination of a tumor type that has a high potential for CNS spread and a treatment that does not penetrate the CNS but is very effective outside of the CNS creates the opportunity for CNS disease to become a major clinical problem. As an example, the introduction of trastuzumab has altered the natural history of patients with HER2-positive breast cancer, and unmasked CNS metastases as a potential sanctuary site. It is anticipated that this HER2 paradigm is applicable across tumor types, as patients live longer with advanced cancer. In the next decade, there will be a greater need to conduct carefully designed trials of both cytotoxic chemotherapeutic agents and targeted agents, either alone, or in combination, with specific CNS end points.

In conclusion, BM patients with breast cancer are an heterogenous group of patients. BM patients with HER-2 overexpressing tumors treated by trastuzumab appears to be a clearly distinct subroup of patients who can expect a median survival time of about 20 months and a1-year survival rate of 60%. This information may be useful to tailor the therapy for subgroups of patients, to define homogeneous cohorts for prospective randomized trials, and to identify more precisely patients with relative good prognosis who could be treated with innovative approaches, in order to obtain better intra cerebral control, in a manner that could minimize late effects.

The authors declare that they have no competing interests.

The authors indicate no potential conflict of interest.

RLS and CM designed coordinated the study and drafted the wrote the manuscript. LJ and EMF performed the statistical analysis. MG, YK PC, JG and AL participated in its design and coordination and helped draft the manuscript. All authors read and approved the final manuscript.