Prognosis of HER2-Low vs HER2-Negative Breast Cancer

Get Permission

In an analysis of National Cancer Database data reported in JAMA Oncology, Peiffer et al found “minimal prognostic differences” between HER2-low vs HER2-negative breast cancer, with the findings not supporting classification of HER2-low disease as a distinct disease subtype. 

Study Details

The retrospective cohort study included data from the National Cancer Database on 1,136,016 patients diagnosed with invasive breast cancer between January 2010 and December 2019 who had HER2-negative disease and available immunohistochemistry results. HER2-low tumors were defined as those with an immunohistochemistry score of 1+ or score of 2+ with negative in situ hybridization test results. Patients received standard therapies according to routine clinical practice. The primary outcome measures in the current analysis were overall survival and pathologic complete response (pCR) in analyses adjusted for age, sex, race, and ethnicity, Charlson-Deyo Comorbidity Index score, treatment facility type, tumor grade, tumor histology, hormone receptor status, and cancer stage. A total of 99,783 patients had available pathologic outcomes after neoadjuvant therapy and were included in the analysis of pCR rates.

This large-scale retrospective cohort analysis found minimal prognostic differences between [HER2]-low and [HER2]-negative breast cancer... These findings do not support the classification of [HER2]-low breast cancer as a unique disease entity.
— Peiffer et al

Tweet this quote

Key Findings

Among the 1,136,016 patients, 392,246 (34.5%) had HER2-negative and 743,770 (65.5%) had HER2-low disease. Mean age was 62.1 years (standard deviation [SD] = 13.2 years) in the HER2-negative group and 62.5 years (SD = 13.0 years) in the HER2-low group.  

Higher estrogen receptor expression was associated with increased likelihood of HER2-low disease (adjusted odds ratio [aOR] = 1.15 per 10% increase, P < .001), whereas increased progesterone receptor expression was associated with decreased likelihood (aOR = 0.95 per 10% increase, P < .001).

Compared with White patients (66.1%), numerically fewer Black patients (62.8%) and Hispanic patients (61.0%) had HER2-low disease.   

Among patients with data available on response to neoadjuvant therapy, pCR was observed in 9,812 (16.3%) of 60,095 HER2-low patients vs 9,372 (23.6%) of 39,688 HER2-negative patients (aOR = 0.89, 95% confidence interval [CI] = 0.86–0.92, P < .001).

Median follow-up was 54 months (interquartile range = 33–80 months). HER2-low status was associated with improvements in overall survival for stage III (adjusted hazard ratio [aHR] = 0.92, 95% CI = 0.89­­–0.96, P < .001) and stage IV (aHR = 0.91, 95% CI = 0.87–0.96, P < .001) triple-negative breast cancer. The differences amounted to a 2.0% increase in 5-year overall survival in stage III disease and a 0.4% increase in stage IV disease.

The investigators concluded, “This large-scale retrospective cohort analysis found minimal prognostic differences between [HER2]-low and [HER2]-negative breast cancer. These findings suggest that, moving forward, outcomes in [HER2]-low breast cancer will be driven by [HER2]-directed antibody-drug conjugates, rather than intrinsic differences in biological characteristics associated with low-level [HER2] expression. These findings do not support the classification of [HER2]-low breast cancer as a unique disease entity.”

Frederick M. Howard, MD, of the Section of Hematology/Oncology, Department of Medicine, University of Chicago, is the corresponding author for the JAMA Oncology article.

Disclosure: This study was supported by the Breast Cancer Research Foundation and American Society of Clinical Oncology/Conquer Cancer Foundation and others. For full disclosures of the study authors, visit

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.