HER2 Protein and Gene Variation between Primary and Metastatic Breast Cancer: Significance and Impact on Patient Care

Abstract

Purpose: To analyze HER2 status in primary breast cancer (PBC) compared with correspondent metachronous metastases and to investigate whether BC phenotype may be predictive of change in HER2 expression.Experimental Design: HER2 was investigated by immunohistochemistry, silver in situ hybridization (SISH), and FISH, in a series of 137 tumors, building up a tissue microarray to concurrently analyze each single PBC and metastatic (MBC) on the same slide.Results: HER2 status was discordant in 14 cases (10%): 12 negative in PBC and positive in metastases and two positive in PBC and negative in metastases (P ¼ 0.04). These findings were confirmed by a PCR based test termed Multiplex Ligation-dependent Probe Amplification (MLPA). HER2 status changed in hormone receptor-positive BC more frequently than in negative ones (P ¼ 0.002). In addition, we evaluated HER2 gene and chromosome 17 copy number by SISH in the 123 cases with unchanged HER2 status during progression. We found consistent HER2 gene copy number stability in the 100 nonamplified cases. Conversely, of the 23 amplified PBC, 13 (57%) demonstrated a significant increase in the HER2 gene and chromosome 17 copy number in their paired metastases (P ¼ 0.01), as defined by SISH (k ¼ 0.54, P < 0.0001) and MLPA. Patients who changed HER2 status from negative to positive, presented significant longer time to progression when treated with trastuzumab compared to those who were untreated (P ¼ 0.04).Conclusions: When feasible, HER2 reassessment in metastatic lesions should be carefully taken into account, especially for metastases coming from primary hormone receptor-positive BC.

Intratumoral heterogeneity of HER2 gene amplification in breast cancer: its clinicopathological significance

“…[8][9][10] However, several studies have reported significant discordance. [11][12][13][14] Some studies have suggested that HER2 gene amplification can be acquired during tumor progression and that this could be a cause of this discordance. 12,13 Others have demonstrated primary intratumoral heterogeneity of both HER2 expression and HER2 gene amplification.…”

Testing for HER2 in Breast Cancer: Current Pathology Challenges Faced in Canada

“…A separate study of 137 primary breast tumours and metachronous metastases revealed discordant her2 status in only 10% of cases (n = 14). Given that some of the patients had received prior trastuzumab, it is interesting to note that a pairing of her2-negative primary tumour with her2-positive metastasis was significantly more common than was her2-positive primary tumour with her2-negative metastasis (12 cases vs. 2 cases, p = 0.04) 48 . However, no dedicated analysis was performed to assess the stability of her2 status according to trastuzumab pretreatment.…”

Positron Emission Tomography Imaging with 18F-Labeled ZHER2:2891 Affibody for Detection of HER2 Expression and Pharmacodynamic Response to HER2-Modulating Therapies

“…However, this can be intricate as HER2 expression may vary through progression from primary to secondary disease with locoregional and distant recurrences often not being amenable to biopsy (11). Furthermore, recent studies have highlighted spatial heterogeneity as a potential source of incorrect assessment (12).…”