Concordance of HER2 in primary tumor and leptomeningeal metastases: now what?

Breast cancer is the solid tumor most commonly associated with leptomeningeal metastases (LM) [1]. Although the absolute incidence is low, patients with LM often present with debilitating symptoms, including pain, headache, cranial nerve palsies, limb weakness, and alterations in mental status, and therefore the clinical implications are significant [2]. Unfortunately, despite multimodality therapy, the prognosis is generally poor. At present, standard therapies for LM do not take into account tumor subtype, though targeted, subtype-specific therapies are increasingly being employed in the treatment of patients with advanced breast cancer without active CNS involvement. In this context, as reported in this issue of Breast Cancer Research and Treatment, Park and colleagues set out to describe concordance in HER2 status between primary tumors and subsequent LM. Notably, of 49 patients diagnosed with LM on the basis of positive cytology at their institution, 32 patients had inadequate cellularity (less than 20 malignant cells per slide) for testing by fluorescence in situ hybridization (FISH), and one patient was excluded because of lack of information on the primary tumor, leaving only 16 cases (33%) for analysis. Additionally, although immunohistochemistry (IHC) for HER2 was available for primary tumors in all cases, FISH results from the primary tumor were only available for comparison in two cases (who had 2? IHC). Nevertheless, and not unexpectedly, the authors observed a high level of concordance for HER2 in LM, compared to matched, primary tumors. Specifically, of four patients with evidence of HER2 amplification in malignant cells from the CSF, all four were IHC 3? in the primary tumor. Eleven of 12 HER2-negative cases were also concordant. Closer examination of the data indicates that the single ‘‘discordant’’ case occurred in the setting of IHC 2? and FISH ratios that were quite similar between primary and LM (HER2 to CEP17 ratio = 2.1 and 1.74, respectively). Given the potential for tumor heterogeneity and sampling issues related to the limited amount of CSF sample, it is not clear that the case truly represents a functional shift in tumor subtype. This study adds to the literature indicating high concordance of HER2 expression between primary tumors and their corresponding metastases. In a series of 29 patients with breast cancer who had matched specimens from primary tumor and brain metastasis (BM), the overall concordance rate for HER2 was 97% [3]. A similar study of 43 patients treated at Memorial Sloan Kettering Cancer Center revealed no significant differences in ER, PR, HER2, EGFR, or CK5/6 expression between paired primary and BM specimens [4]. Looking more generally at other sites of metastasis, the data indicate conservation of HER2 status in most cases [5]. MacFarlane et al. [6] examined 160 paired specimens and found only nine cases (5.6%) in which the HER2 status changed. Liedtke et al. [7] examined 211 paired specimens and found that the correlation coefficient for HER2 FISH was 0.895. Even when multiple metastases are tested in a single patient, HER2 status is generally conserved across lesions [8]. Collectively, the data substantiate the concept that HER2 is a central player in tumor maintenance, including in patients with CNS relapse. This is an invited commentary to article doi:10.1007/s10549-009-0627-3.