HER2-low should not be a distinct biologic subtype of breast cancer because it has no prognostic significance, according to a presentation at ESMO Breast Cancer 2022. 

Researchers observed clinicopathologic differences between tumors with low HER2 expression and those with no HER2 expression. 

However, there were no significant differences in response or survival outcomes between the 2 groups after researchers adjusted for hormone receptor (HR) status.

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In the past, it hasn’t been clear whether low HER2 expression is associated with distinct biology or prognosis, when controlling for HR status and other confounders, said presenter Paolo Tarantino, MD, of Dana Farber Cancer Institute in Boston. 

With this in mind, Dr Tarantino and colleagues set out to characterize clinicopathologic features and prognosis in patients with HER2-low early breast cancer

The study included 5235 patients who underwent surgery for breast cancer at Dana-Farber Brigham Cancer Center in Boston between January 2016 and March 2021. 

Patients were divided into 2 cohorts — HER2-low and HER2-zero. HER2-low patients had a HER2 immunohistochemistry (IHC) score of 1+ or 2+ with negative in situ hybridization. HER2-zero patients had an IHC score of 0. 

Overall, 55% of patients were HER2-low (n=2917) and 45% were HER2-zero (n=2318). Among the HR-positive patients, 58% were HER2-low (2643/4538). In patients with triple-negative breast cancer (TNBC), 39% were HER2-low (274/697).

Clinicopathologic Features

The researchers found significant differences in clinicopathologic features between the HER2-low and HER2-zero groups. HER2-low patients were more likely to have estrogen receptor (ER)-positive disease (P <.001), be premenopausal (P =.02), and have received endocrine therapy (P <.001).

HER2-low patients were less likely to have BRCA1/2 or other germline mutations (P =.001), have lobular histology (P <.001), have grade III tumors (P <.001), and have received chemotherapy (P <.001). 

Dr Tarantino noted that ER expression was positively associated with HER2-low expression (P <.001). There was a progressive increase in the rate of HER2-low tumors with increasing ER expression, from 40% in ER-negative patients to 62% in patients with very high ER expression (>95%). 

Response and Survival Outcomes

Among patients who received neoadjuvant chemotherapy (n=675), those with HER2-low tumors had a lower pathologic complete response (pCR) rate than those with HER2-zero tumors — 16% and 26%, respectively (P =.002). 

However, there was no significant difference in pCR rates between the HER2-low and HER2-zero groups after adjusting for HR expression. 

There was no significant difference for TNBC patients (P =.40), ER-low patients (P =0.46), HR-positive patients (P =.078), or an HR-positive cohort in which ER-low patients were excluded (P =.27). 

In an unadjusted analysis, survival outcomes were significantly better for patients with HER2-low tumors. These patients had a significant improvement in disease-free survival (hazard ratio [HR], 1.41; P =.02), distant disease-free survival (HR, 1.40; P =.02), and overall survival (HR, 1.48; P =.04). 

However, after adjusting for HR expression, there were no significant differences between the HER2-low and HER2-zero cohorts for disease-free survival (HR, 1.19; P =.24), distant disease-free survival (HR, 1.18; P =.26), or overall survival (HR, 1.20; P =.35). 

Likewise, there were no significant survival differences between the 2 cohorts when the researchers looked at the HR-positive population and the TNBC population separately.

“[O]ur results do not support HER2-low as a distinct biologic subtype of breast cancer,” Dr Tarantino concluded. 

Disclosures: Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.


Tarantino P, Jin Q, Tayob N, et al. Prognostic and biologic significance of HER2-low expression in early breast cancer. ESMO Breast Cancer 2022; May 3-5, 2022. Abstract 1MO.