The dynamics of HER2-low expression during breast cancer progression

Purpose Low HER2 expression is emerging as an actionable target for the treatment of breast cancer (BC) with the antibody drug conjugate Trastuzumab deruxtecan. The aim of the study was to characterize the dynamics of HER2 expression during BC progression. Methods We evaluated the evolution of HER2 expression in 171 paired primary and metastatic BCs (pBCs/mBCs) by including the HER2-low category . Results The proportions of HER2-low cases were 25.7% in pBCs and 23.4% in mBCs, respectively, while those of HER2-0 cases were 35.1% and 42.7%, respectively. The overall conversion rate between HER2-0 and HER2-low was 31.7%. HER2-low switching to HER2-0 was more frequent than the reverse (43.2% vs. 23.3%; P = 0.03). Two (3.3%) and 9 (20.5%) cases of pBCs with a HER2-0 and a HER2-low status, respectively, were converted to HER2-positive mBCs. In contrast, 10 (14.9%) HER2-positive pBCs were converted to HER2-0 and an identical number to HER2-low mBCs, respectively, significantly higher than that when compared to the HER2-0 to HER2-positive ( P = 0.03), but not HER2-low to HER2-positive conversion. No significant difference was found when comparing the conversion rates among the common organs of relapse. Of the 17 patients with multiorgan metastases, 41.2% had discordance among the different sites of relapse. Conclusions HER2-low BCs constitute a heterogeneous group of tumors. Low HER2 expression is dynamic, with significant discordance between primary tumors and advanced disease as well as the distant sites of relapse. Repeat biomarker studies from advanced disease are warranted in making appropriate treatment plans in the pursuit of precision medicine.