HER2–Low Positive and HER2-Zero Breast Cancers Are Clinically Distinct

HER2 expression level in breast cancer is demonstrably associated with a variety of clinical features and correlates with treatment response rates. However, it is not known whether completely HER2-negative breast cancer—defined by an immunohistochemistry score of 0 (IHC0)—differs significantly from breast cancer with very low (IHC1⁺ or IHC2⁺ and in situ hybridization negative) expression of HER2. To evaluate this, Denkert and colleagues performed a prospective cohort analysis including 2,310 patients with breast cancer that expressed little (IHC1⁺ or IHC2⁺ and in situ hybridization negative; 47.5% of patients) to no (ICH0; 52.5% of patients) HER2 who were enrolled in four different clinical trials investigating the use of neoadjuvant chemotherapy. A substantial difference in hormone receptor expression between the two groups was found, with 63.3% of HER2-zero tumors being hormone receptor–negative and 36% of HER2–low positive tumors being hormone receptor–negative. When compared with complete absence of HER2 expression, low positivity for HER2 was associated with signs of reduced aggressiveness, including lower cell proliferativity, lower tumor grade, and fewer TP53 mutations. This may explain the additional findings that HER2–low positive tumors were less likely than HER2-zero tumors to exhibit complete pathologic responses to neoadjuvant chemotherapy and that disease-free and overall survival were superior in patients with HER2–low positive tumors. Specifically, in patients with HER2–low positive disease, three-year disease-free survival and overall survival rates were 83.4% and 91.6%, respectively, whereas in patients with HER2-zero disease, three-year disease-free survival and overall survival rates were lower at 76.1% and 85.8%, respectively. Although additional standardization would be required to firmly establish guidelines for delineating HER2-zero and HER2–low positive breast cancer, this study suggests that HER2–low positive breast cancer may represent a clinical entity distinct from both HER2-zero and classic HER2⁺ breast cancer.

Denkert C, Seither F, Schneeweiss A, Link T, Blohmer JU, Just M, 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;22:1151–61.

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