HER2-low-positive breast cancer: evolution from primary tumor to residual disease after neoadjuvant treatment

Abstract

Approximately a half of breast tumors classified as HER2-negative exhibit HER2-low-positive expression. We recently described a high instability of HER2-low-positive expression from primary breast cancer (BC) to relapse. Previous studies reporting discordance in HER2 status between baseline biopsy and residual disease (RD) in patients undergoing neoadjuvant treatment did not include the HER2-low-positive category. The aim of this study is to track the evolution of HER2-low-positive expression from primary BC to RD after neoadjuvant treatment. Patients undergoing neoadjuvant treatment with available baseline tumor tissue and matched samples of RD (in case of no pCR) were included. HER2-negative cases were sub-classified as HER2-0 or HER2-low-positive (IHC 1+ or 2+ and ISH negative). Four-hundred forty-six patients were included. Primary BC phenotype was: HR-positive/HER2-negative 23.5%, triple-negative (TN) 35%, HER2-positive 41.5%. HER2-low-positive cases were 55.6% of the HER2-negative cohort and were significantly enriched in the HR-positive/HER2-negative vs. TN subgroup (68.6% vs. 46.8%, p = 0.001 χ2 test). In all, 35.3% of non-pCR patients (n = 291) had a HER2-low-positive expression on RD. The overall rate of HER2 expression discordance was 26.4%, mostly driven by HER2-negative cases converting either from (14.8%) or to (8.9%) HER2-low-positive phenotype. Among HR-positive/HER2-negative patients with HER2-low-positive expression on RD, 32.0% and 57.1% had an estimated high risk of relapse according to the residual proliferative cancer burden and CPS-EG score, respectively. In conclusion, HER2-low-positive expression showed high instability from primary BC to RD after neoadjuvant treatment. HER2-low-positive expression on RD may guide personalized adjuvant treatment for high-risk patients in the context of clinical trials with novel anti-HER2 antibody-drug conjugates.

Efficacy evaluation of neoadjuvant chemotherapy in patients with HER2-low expression breast cancer: A real-world retrospective study

“…Federica Miglietta et al. performed a retrospective study of 488 cases and obtained a consistent result that a lower proportion of pCR in HER2-low breast cancer patients (21.4%) after NACT than HER2-negative ones (33.6%) ( 27 ). Furthermore, another study including four prospective neoadjuvant clinical trials have reported analogous findings (pCR rates: 29.2% (HER2-low) vs 39.0% (HER2-negative)), which also showed that the proportion of pCR was significantly lower in HER2-low tumors versus HER2-negative tumors in the ER-positive subgroup ( P = 0.024) but not in the ER-negative subgroup ( P = 0.21).…”

Treatment options for patients with human epidermal growth factor 2-positive breast cancer brain metastases: A systematic review and meta-analysis

“…ADC drugs improve survival not only in HER2-positive breast cancer patients, but also in patients with low expression of HER2. HER2-low-expressing breast cancer is a heterogeneous group of HER2-low-expressing population ( 20 , 21 ). The results of the DESTINY-Breast04 study showed that compared to the physician-selected treatment group, patients on trastuzumab deruxtecan with low expression of HER2 showed unprecedented statistically significant and clinically meaningful improvements in PFS and OS.…”

Prognostic Value of the Evolution of HER2-Low Expression after Neoadjuvant Chemotherapy

“…Discrepancies are also found in the influence of the HER2-low status on the pathological complete response (pCR) rate of patients receiving neoadjuvant chemotherapy (NACT) [12,13,15]. The diverse evolution of HER2 status before and after NACT have been observed in previous studies [16][17][18]. These controversial results suggest that the clinicopathological characteristics and prognostic value of HER2-low patients with early BC receiving NACT warrant further research.…”