Loss of Her2+ in Metastatic Sites of Her2+ BC

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J Clin Oncol. 2012 Feb 20;30(6):593-599, N Niikura, J Liu, N Hayashi, E Mittendorf, Y Gong, S Palla, Y Tokuda, A Gonzalez-Angulo, G Hortobagyi, N Ueno

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In this retrospective analysis, chemotherapy, but not trastuzumab, was associated with increased loss of HER2-positivity in metastases in patients with HER2+ breast cancer, and this discordance was associated with a poorer prognosis

EXPERT COMMENTARY

Lee S. Schwartzberg, MD, FACP

Changes in molecular phenotype (ER, PR, and HER2) between primary and metastatic breast cancer have increasingly been recognized. It remains controversial how often the phenomenon truly occurs and what are the driving forces behind a phenotypic change. For instance, is it due to genomic instability, treatment effects, heterogeneous subclones in the primary tumor, or all of the above and more? The current study reviewed the large MD Anderson database of patients with breast cancers, focusing on loss of HER2 overexpression, from positive in the primary tumor to negative in the biopsied metastatic tumor. The investigators found that 24% of HER2+ cancers became HER2− over time. Chemotherapy pretreatment, either in the adjuvant or metastatic setting, seemed to increase the rate of negative HER2, but prior trastuzumab usage did not, a somewhat counterintuitive observation. Interestingly, patients with concordant HER2 status between primary and metastatic tumor sites had better overall survival than those with discordant HER2 status. This retrospective study suffers from many biases inherent to the observational nature of the analysis. The time has come for prospective trials to address the important questions related to phenotypic change in both directions in breast cancer.

SUMMARY

OncologySTAT Editorial Team

Metastases may differ from primary breast tumors in the status of human epidermal growth factor receptor-2 (HER2). Some studies have suggested that HER2-targeted therapies, such as trastuzumab, may alter HER2 status in primary tumors. This retrospective study evaluated the effect of trastuzumab on the likelihood of HER2 discordance between primary and metastastic tumors in patients with HER2-positive (HER2+) breast cancer, and the effects of HER2 discordance on overall survival (OS).

The study utilized a database at a single institution to identify patients with primary HER2+ breast cancer who had metastases. In 182 of these patients, the HER2 status had been determined for the metastases. Testing methodologies included immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH).

Of the 182 patients, 43 (24%) had HER2-negative metastatic tumors. Discordance rates did not differ significantly between patients who did or did not receive trastuzumab (P = .296). However, more patients who received chemotherapy before their metastatic tumor biopsies had discordant HER2 status, compared with those who had not received chemotherapy before the biopsies (27% vs 10%; P = .022), including among patients who had not received trastuzumab (P = .003). Discordance rates did not differ significantly among patients based on when metastases were diagnosed (at presentation vs at recurrence; P = .077), among those with distant vs local metastases (P = .212), or among those with hormone receptor–positive vs hormone receptor–negative tumors (P = .865).

The relationship between HER2+ discordance and OS was evaluated among 168 patients with distant metastases. Of note, patients with discordant HER2 status were significantly older than those without discordant HER2 status (P = .013). Premenopausal patients (P = .023) and those with grade 3 disease (P <.001) were more common in the concordant group compared with the discordant group. OS was significantly longer in the concordant group compared with the discordant group (hazard ratio [HR], 0.47; P = .003). On multivariate analysis, after controlling for age, tumor grade, and menopausal status, HER2 status continued to have a significant effect on OS (HR, 0.36; P <.001). This effect was independent of trastuzumab status.

Chemotherapy, but not trastuzumab, was associated with increased loss of HER2-positivity in metastases in patients with HER2+ breast cancer, and this discordance was associated with a poorer prognosis. However, inconsistencies in testing methodology (IHC vs FISH) may have resulted in a selection bias, so further study is needed.


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