July 2021: Clinical and molecular characteristics of HER2-low-positive breast cancer

The development of anti-HER2 antibody-drug conjugates, including trastuzumab deruxtecan and trastuzumab duocarmazine, opens new therapeutic options for patients with breast cancer, including patients with low expression of HER2. This study investigated the hypothesis that tumors with low-positive HER2 expression have different biological and clinical outcome characteristics compared with tumors that are completely HER2-negative (HER2-zero).

To address this hypothesis, a cohort of patients who were treated with neoadjuvant combination chemotherapy in four prospective neoadjuvant clinical trials (GeparSepto, GeparOcto, GeparX, and Gain-2 neoadjuvant) were evaluated for biologically relevant parameters, including hormone receptor status, tumor proliferation, tumor-infiltrating lymphocytes (TILs), and somatic and germline mutations of clinically relevant genes. A total of 2310 patients with HER2 non-amplified primary breast cancer were included in the pooled analysis. Central HER2 testing was done prospectively before random assignment of participants in all trials. HER2-low-positive status was defined as immunohistochemistry (IHC) 1+ or IHC2+/in-situ hybridization negative and HER2-zero was defined as IHC0, based on the American Society of Clinical Oncology/College of American Pathologists guidelines. Survival data were available for 1694 patients (from all trials except GeparX) with a median follow-up of 46.6 months (IQR 35.0–52.3). Endpoints were pathological complete response (pCR), disease-free survival (DFS), and overall survival (OS).

A total of 1098 (47.5%) of 2310 tumors were HER2-low-positive and 1212 (52.5%) were HER2-zero. Significant differences between HER2-zero and HER2-low-positive tumors were detected for hormone receptor status: 703 (64.0%) of 1098 patients with HER2-low-positive tumors were hormone receptor-positive versus 445 (36.7%) of 1212 patients with HER2-zero tumors (p<0.001) as well as proliferation rate (measured by Ki-67), grading, histopathological type and nodal status. A significant difference was also seen for patient age as a continuous variable but not as a categorical variable; no differences were seen for T-stage and stromal TILs.
HER2-low-positive tumors had a significantly lower pCR rate than HER2-zero tumors (321 [29.2%] of 1098 vs 473 [39.0%] of 1212, p=0.0002). With regards to hormone receptor status, pCR was also significantly lower in HER2-low-positive tumors versus HER2-zero tumors in the hormone receptor-positive subgroup (123 [17.5%] of 703 vs 105 [23.6%] of 445, p=0.024), but not in the hormone receptor-negative subgroup (198 [50.1%] of 395 vs 368 [48.0%] of 767, p=0.21). Patients with HER2-low-positive tumors had significantly longer survival than patients with HER2-zero tumors (3-year DFS: 83.4% [95%CI 80.5-85.9] vs 76.1% [95%CI 72.9-79.0]; stratified log-rank test p=0.008; 3-year OS: 91.6% [95%CI 84.9-93.4] vs 85.8% [95%CI 83.0-88.1]; stratified log-rank test p=0.0016). Patients with hormone receptor-negative tumors had also significantly improved survival (3-year DFS: 84∙5% [95%CI 79∙5–88∙3] vs 74∙4% [95%CI 70.2-78.0]; stratified log-rank test p=0∙0076; 3-year OS: 90∙2% [95%CI 86∙0–93∙2] vs 84∙3% [95%CI 80.7-87.3], stratified log-rank test p=0∙016) in contrast to patients with hormone receptor-positive tumors (3-year DFS 82∙8% [95%CI 79∙1-85∙9] vs 79∙3% [95%CI 73∙9-83∙7]; stratified log-rank test p=0.39; 3-year OS 92.3% [95%CI 89.6-94.4] vs 88.4% [95%CI 83∙8-91∙8]; stratified log-rank test p=0∙13).

In general, the biological model of breast cancer has been based on the subtypes hormone receptor-positive/HER2-negative, HER2-positive, and triple-negative breast cancer. This study supports the view that additional clinically relevant subtypes of breast cancer exist. In breast cancer, these new subtypes can be distinguished by standardized pathological assessment of hormone receptors and HER2 with particular focus on HER2-low-positive tumors. The HER2-low-positive tumors have a specific biology and show differences in response to therapy and prognosis, which is particularly relevant in therapy-resistant, hormone receptor-negative tumors. Hence, these findings provide a basis for a better understanding of the biology of breast cancer subtypes and the refinement of future diagnostic and therapeutic strategies.

Denkert C, Seither F, Schneeweiss A, et al. Clinical and molecular characteristics of HER2-low-positive breast cancer: pooled analysis of individual patient data from four prospective, neoadjuvant clinical trials. Lancet Oncol. 2021; doi: 10.1016/S1470-2045(21)00301-6

• PubMed Link: https://pubmed.ncbi.nlm.nih.gov/34252375/