Clinicopathologic Characteristics and Prognosis of ERBB2-Low Breast Cancer Among Patients in the National Cancer Database

Abstract

ImportanceGiven conflicting results regarding the prognosis of erb-b2 receptor tyrosine kinase 2 (ERBB2; formerly HER2 or HER2/neu)–low breast cancer, a large-scale, nationally applicable comparison of ERBB2-low vs ERBB2-negative breast cancer is needed.ObjectiveTo investigate whether ERBB2-low breast cancer is a clinically distinct subtype in terms of epidemiological characteristics, prognosis, and response to neoadjuvant chemotherapy.Design/Participants/SettingThis retrospective cohort study was conducted using the National Cancer Database, including 1 136 016 patients in the US diagnosed with invasive breast cancer from January 1, 2010, to December 31, 2019, who had ERBB2-negative disease and had immunohistochemistry results available. ERBB2-low tumors were classified as having an immunohistochemistry score of 1+, or 2+ with a negative in situ hybridization test. Data were analyzed from November 1, 2021, through November 30, 2022.ExposuresStandard therapy according to routine clinical practice.Main Outcomes and MeasuresThe primary outcomes were overall survival (OS), reported as adjusted hazard ratios (aHRs), and pathologic complete response, reported as adjusted odds ratios (aORs), for ERBB2-negative vs ERBB2-low breast cancer, controlling for age, sex, race and ethnicity, Charlson-Deyo Comorbidity Index score, treatment facility type, tumor grade, tumor histology, hormone receptor status, and cancer stage.ResultsThe study identified 1 136 016 patients (mean [SD] age, 62.4 [13.1] years; 99.1% female; 78.6% non-Hispanic White), of whom 392 246 (34.5%) were diagnosed with ERBB2-negative and 743 770 (65.5%) with ERBB2-low breast cancer. The mean (SD) age of the ERBB2-negative group was 62.1 (13.2) years and 62.5 (13.0) years for the ERBB2-low group. Higher estrogen receptor expression was associated with increased rates of ERBB2-low disease (aOR, 1.15 per 10% increase). Compared with non-Hispanic White patients, of whom 66.1% were diagnosed with ERBB2-low breast cancer, fewer non-Hispanic Black (62.8%) and Hispanic (61.0%) patients had ERBB2-low disease, although in non-Hispanic Black patients this was mediated by differences in rates of triple-negative disease and other confounders. A slightly lower rate of pathologic complete response was seen in patients with ERBB2-low disease vs patients with ERBB2-negative disease on multivariable analysis (aOR, 0.89; 95% CI, 0.86-0.92; P < .001). ERBB2-low status was also associated with small improvements in OS for stage III (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, although this amounted to only a 2.0% (stage III) and 0.4% (stage IV) increase in 5-year OS.Conclusions and RelevanceThis large-scale retrospective cohort analysis found minimal prognostic differences between ERBB2-low and ERBB2-negative breast cancer. These findings suggest that, moving forward, outcomes in ERBB2-low breast cancer will be driven by ERBB2-directed antibody-drug conjugates, rather than intrinsic differences in biological characteristics associated with low-level ERBB2 expression. These findings do not support the classification of ERBB2-low breast cancer as a unique disease entity.

Survival Outcomes in Patients With Hormone Receptor–Positive Metastatic Breast Cancer With Low or No ERBB2 Expression Treated With Targeted Therapies Plus Endocrine Therapy

“…Those findings are supportive of previously published data that suggest that low ERBB2 expression is not associated with CDK4/6i benefit 15,16 and that it is not a distinct entity in breast cancer by clinical factors assessed so far. 13,17 One reason for this lack of statistical difference is that the pathologic distinction between no and low ERBB2 expression is difficult given that the testing methods may be associated with significant variability in ERBB2 expression 10 and highly dependent on the reading pathologist. 7 Additionally, it remains possible that ERBB2 expression may not be associated with benefit from the newly approved trastuzumab deruxtecan given that the DAISY (…”

“…In fact, our study suggests that low ERBB2 expression status has no prognostic value and is not associated with distinctive clinicopathologic features compared with patients with HR-positive mBC with no ERBB2 expression treated with TT and ET. Those findings are supportive of previously published data that suggest that low ERBB2 expression is not associated with CDK4/6i benefit and that it is not a distinct entity in breast cancer by clinical factors assessed so far …”

Classification of Breast Cancer According to ERBB2 Immunohistochemistry Scores

“…To the Editor While we were impressed by the size (n = 1 136 016) of the recent study by Peiffer et al published in JAMA Oncology that analyzed clinical data from the National Cancer Database (NCDB), this large-scale retrospective cohort of patients with ERBB2-negative and ERBB2-low disease used a legacy ERBB2 (formerly HER2 or HER2/neu) immunohistochemistry (IHC) assay read by pathologists. Although the authors report minimal prognostic differences in terms of overall survival between ERBB2-low (IHC 1+ or 2+/in situ hybridization negative) and ERBB2-negative (IHC 0) groupings, they acknowledge that these legacy assays were not designed to distinguish ERBB2-low from ERBB2-negative tumors.…”

“…Although the authors report minimal prognostic differences in terms of overall survival between ERBB2-low (IHC 1+ or 2+/in situ hybridization negative) and ERBB2-negative (IHC 0) groupings, they acknowledge that these legacy assays were not designed to distinguish ERBB2-low from ERBB2-negative tumors. We think this limitation led them to a false conclusion that “these findings do not support the classification of ERBB2-low breast cancer as a unique disease entity.”…”

Classification of Breast Cancer According to ERBB2 Immunohistochemistry Scores—Reply

“…In Reply We appreciate the insightful comments by Robbins and colleagues regarding the appropriateness of immunohistochemistry (IHC) to define ERBB2-low and ERBB2-negative breast cancer in our study . ERBB2-low has been defined as IHC 1+ or 2+ with negative in situ hybridization testing in the US Food and Drug Administration labeling for trastuzumab deruxtecan, and this categorization is widely recognized in national guidelines.…”