Is HER2 ultra-low breast cancer different from HER2 null or HER2 low breast cancer? A study of 1363 patients

Abstract Objective This study aims to analyze whether there are any differences in clinicopathological features and prognosis between HER2 ultra-low, HER2-null and HER2 low expression in Chinese breast cancer (BC) patients. Methods The clinicopathological data of 1363 HER2 negative BC patients were retrospectively collected (from January 2018 to December 2019). HER2 status was further classified into HER2-null, HER2 ultra-low and HER2-low. HER2-null expression is defined as infiltrating cancer cells completely free of staining. HER2 ultra-low expression is defined as ≤ 10% of infiltrating cancer cells showing incomplete and faint/weak membrane staining. HER2-low expression is defined as HER2 IHC 1 + or 2 + with negative ISH assay. Results Of 1363 patients, there were 86 (6.3%) HER2-null patients, 395 (29.0%) HER2 ultra-low patients and 882 (64.7%) HER2-low patients. There were statistically significant differences in histologic type (P = 0.014), histologic grade (P = 0.001), Ki-67 proliferation index (P < 0.001) and postoperative endocrine therapy (P < 0.001) among patients with different HER2 status. In addition, the proportion of hormone receptor (HR) negative BC in HER2-null (72.1%) and HER2 ultra-low (81.0%) was significantly higher than that in HER2-low (12.2%, P < 0.001). The survival analysis showed that HER2 status had no effect on disease-free survival(DFS)in HER2 negative BC patients (log-rank, P = 0.281). However, regardless of HER2 status, HR-positive patients had better DFS than HR-negative patients (log-rank, P = 0.003). Cox multivariate analysis revealed that age (HR [95%CI] = 0.950 [0.928, 0.972], P < 0.001), HR status (HR [95%CI] = 3.342 [1.658, 6.736], P = 0.001) and postoperative endocrine therapy (HR [95%CI] = 0.048 [0.048, 0.023], P < 0.001) were important influencing factors of DFS in HER2-negative BC patients. Conclusion HER2 ultra-low BC patients demonstrated distinct clinicopathological features from HER2-null and HER2-low tumors; while, HER2 status (null, ultra-low or low) had no prognostic value in these HER2 negative BC population. Consistent with the published literature, HR status was an independent prognostic factor for DFS in HER2 negative BC patients.