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Original Investigation
June 23, 2022

Prognostic and Biologic Significance of ERBB2-Low Expression in Early-Stage Breast Cancer

Author Affiliations
  • 1Breast Oncology Program, Dana-Farber Cancer Institute, Boston, Massachusetts
  • 2Harvard Medical School, Boston, Massachusetts
  • 3Division of New Drugs and Early Drug Development, European Institute of Oncology, Istituto di Ricovero e Cura a Carattere Scientifico, Milan, Italy
  • 4Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
  • 5Department of Data Science, Dana-Farber Cancer Institute, Boston, Massachusetts
  • 6Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts
  • 7Division of Breast Surgery, Department of Surgery, Brigham and Women’s Hospital, Boston, Massachusetts
JAMA Oncol. 2022;8(8):1177-1183. doi:10.1001/jamaoncol.2022.2286
Key Points

Question  Is ERBB2 (formerly HER2)–low breast cancer a distinct biologic and prognostic subtype?

Findings  In this cohort study of 5235 patients with ERBB2-negative invasive breast cancer, most clinicopathologic differences found between ERBB2-low and ERBB2-0 breast cancers were associated with hormone receptor (HR) expression and ERBB2-low expression had no prognostic significance when adjusting for HR status. ERBB2-low and estrogen receptor (ER) expression were found to be positively associated, with most ER-low–expressing tumors being ERBB2-0 and most ER-high–expressing tumors being ERBB2-low.

Meaning  These results did not support the interpretation of ERBB2-low as a distinct biologic subtype of breast cancer.


Importance  It is unclear whether ERBB2-low breast cancer should be considered an individual biologic subtype distinct from ERBB2-0 breast cancer.

Objective  To investigate whether low ERBB2 expression is associated with distinct clinicopathologic characteristics and prognosis among patients with hormone receptor (HR)-positive and triple-negative breast cancer (TNBC).

Design, Setting, and Participants  This cohort study was conducted using data from a prospectively maintained institutional database on all consecutive patients with breast cancer undergoing surgery between January 2016 and March 2021 at Dana-Farber Brigham Cancer Center. The study included 5235 patients with stage I through III, ERBB2-negative invasive breast cancer. Tumors were classified as ERBB2-low if they had an ERBB2 immunohistochemical (IHC) score of 1+ or 2+ with negative in situ hybridization assay and ERBB2-0 if they had an ERBB2 IHC score of 0. Data were analyzed from September 2021 through January 2022.

Exposures  Standard treatment according to institutional guidelines.

Main Outcomes and Measures  Comparison of clinicopathologic characteristics and disease outcomes (pathologic complete response rate [pCR], disease-free survival, distant disease–free survival, and overall survival) between patients with ERBB2-low and ERBB2-0 breast cancer.

Results  Among 5235 patients with ERBB2-negative invasive breast cancer (5191 [99.2%] women; median [range] age at primary surgery, 59.0 [21.0-95.0] years), 2917 patients (55.7%) and 2318 patients (44.3%) had ERBB2-low and ERBB2-0 tumors, respectively. Expression of HR was significantly more common among ERBB2-low compared with ERBB2-0 tumors (2643 patients [90.6%] vs 1895 patients [81.8%]; P < .001). The rate of ERBB2-low tumors increased progressively, from 296 of 739 estrogen receptor (ER)-negative tumors (40.1%) to 31 of 67 ER-low (ie, ER 1%-9%) tumors (46.3%), 37 of 67 ER-moderate (ie, ER, 10%-49%) tumors (55.2%), 2047 of 3542 ER-high (ie, ER, 50%-95%) tumors (57.8%), and 499 of 803 ER–very high (ie, ER > 95%) tumors (62.1%) (P < .001). Among 675 patients receiving neoadjuvant chemotherapy, those with ERBB2-0 tumors experienced higher pCR rates (95 patients [26.8%] vs 53 patients [16.6%]; P = .002). However, there were no statistically significant differences in pCR rate between ERBB2-low and ERBB2-0 tumors when separately analyzing HR-positive, ER-low, HR-positive without ER-low, or TNBC tumors. In exploratory survival analysis, no differences by ERBB2-low expression in disease-free survival, distant disease–free survival, or overall survival were observed among patients with HR-positive tumors or TNBC.

Conclusions and Relevance  The results of this cohort study did not support the interpretation of ERBB2-low breast cancer as a distinct biologic subtype. ERBB2-low expression was positively associated with level of ER expression, and ER-low tumors were enriched among ERBB2-0 tumors, suggesting that, given the worse prognosis of ER-low tumors, they may be associated with confounding of prognostic analyses of ERBB2-low expression.

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