HER2-low-positive and Response to NACT and Prognosis in HER2-negative Non-metastatic BC

Purpose: With the release of promising data from clinical trials of novel anti-HER2 antibody-drug conjugates, there is a new therapeutic direction in HER2-low expression breast cancer (BC). This study aims to evaluate the differences in clinicopathological characteristics of HER2-low-positive and HER2-zero BC, including response to neoadjuvant chemotherapy (NACT) and prognosis.

Methods: Records of HER2-negative (immunohistochemistry [IHC] 0, + 1, or + 2 non-amplified by in situ hybridization [ISH]) patients who received NACT at our cancer center between January 2017 and December 2017 were retrospectively collected. HER2-low-positive was defined as immunohistochemistry (IHC) 1 + or IHC2 + /in-situ hybridization negative and HER2-zero was defined as IHC0. The coprimary objectives were to compare pathological complete response (pCR) and relapse-free survival (RFS) and overall survival (OS) between the two groups. Univariate and multivariable logistic regression models and Cox-proportional hazards models were performed for analysis of the endpoints pCR, RFS, and OS.

Results: A total of 239 [84.5%] of 283 tumors were HER2-low-positive (including 132 [55.2%] HER2-1 + and 107 [44.8%] HER2-2 + /ISH non-amplified) and 44 [15.5%] were HER2-zero. Patients in the HER2-low-positive group had more commonly hormone receptor positivity than HER2-zero patients (188 [78.7%] vs. 19 [43.2%], P = 0.000), but there was no difference between HER2-1 + and HER2-2 + / ISH non-amplified (99 [75.0%] vs. 89 [83.2%], P = 0.125). HER2-zero tumors had a significantly higher pCR rate than HER2-low-positive tumors (15 [34.1%] of 44 vs. 22 [9.2%] of 239, P = 0.000). Pathological complete response was also significantly higher in HER2-zero tumors versus HER2-low-positive tumors in the hormone receptor-negative subgroup (13 [52.0%] of 25 vs. 14 [27.5%] of 51, P = 0.036), but not in the hormone receptor-positive subgroup (2 [10.5%] of 19 vs 8 [4.3%] of 188, P = 0.231). No significant difference was observed in 5-year RFS between the two groups (HR 0.577, 95% CI 0.298-1.118, P = 0.103). However, HER2-low-positive tumors showed significantly better OS than HER2-zero tumors (HR 0.280, 95% CI 0.122-0.697, P = 0.006).

Conclusions: These results suggest that HER2-low-positive tumors have specific biological characteristics according to the hormone receptor status and exhibit different responses to NACT and prognosis.