Comparison of Management and Outcomes in ERBB2-Low vs ERBB2-Zero Metastatic Breast Cancer in France

Key Points Question Does ERBB2-low metastatic breast cancer have a different prognosis than ERBB2-zero metastatic breast cancer? Findings In this cohort study that enrolled 15 054 patients with metastatic breast cancer from the Epidemiological Strategy and Medical Economics database, patients with ERBB2-low metastatic breast cancer had longer survival than did patients with ERBB2-zero metastatic breast cancer (38.0 vs 33.9 months). Meaning These findings suggest that ERBB2-low metastatic breast cancer has a slightly better prognosis compared with ERBB2-zero cancer, which could help guide treatment selection.


Introduction
The ERBB2-low breast cancer (BC) subtype is a newly proposed subtype for patients with tumors that have an immunohistochemistry (IHC) assay score of 1+ or 2+ without ERBB2 gene amplification. 1,2 In clinical practice, in contrast to ERBB2-positive BC (ie, IHC score 3+ or IHC score 2+ with ERBB2 gene amplification), patients with these tumors are currently not candidates for anti-ERBB2 targeted therapy. 3,4 However, interest in this subgroup is growing with the emergence of antibody-conjugated drugs that have shown promising antitumor activity for this subgroup. [5][6][7] Even if patients with ERBB2-low tumors are treated in the same manner as those with ERBB2-zero tumors (ie, tumors with IHC score 0) in accordance with the current guidelines, 3,8 some evidence has suggested that these tumors are distinct. Some retrospective studies in early BC have suggested a worse prognosis, [9][10][11] improved clinical outcomes, 12 or similar clinical outcomes 13,14 compared with ERBB2-zero disease.
Regarding metastatic disease, very few and contradictory data are available. 15,16 Considering the new emerging therapies for ERBB2-low BC, especially in a metastatic setting, a better description of the epidemiology, response to treatment, and outcomes of that population seems important. Our goal was to provide a comprehensive analysis of ERBB2-low metastatic BC (MBC) management and prognosis compared with ERBB2-zero MBC in, to our knowledge, the largest cohort to date.

Study Design
This noninterventional, retrospective cohort study aimed to describe the management and outcomes of patients with ERBB2-zero MBC selected from the Epidemiological Strategy and Medical Economics (ESME) MBC database. The ESME MBC database is a multicenter database that uses a retrospective data collection process (18 French comprehensive cancer centers over 20 sites). This database compiles data from patients' electronic medical records. Patients who started a first-line anticancer treatment for MBC in any of the 18 cancer centers that participated in the ESME Research Program from January 1, 2008, to December 31, 2016, were enrolled. In the present study, we specifically selected patients whose tumor was ERBB2-zero or ERBB2-low, as defined later in this article. The data were compiled until the cutoff date (January 24, 2020), death, or date of last contact (if lost to follow-up). The analysis was approved by an independent ethics committee (Comité De Protection Des Personnes Sud-Est). No formal dedicated informed consent was required; however, all patients had approved the reuse of their electronically recorded data. In compliance with French regulations, the ESME-MBC database was authorized by the French data protection authority.

Tumor Subtype Assessment
Standard guidelines were applied to any analysis performed within the ESME database. ERBB2 and hormone receptor statuses were derived from existing results on metastatic tissue sampling if available or, if unavailable, from the last sampling of early disease. If 2 or more histologic reports were available on the same date, a positive status was considered dominant. No central review was executed. BC was hormone receptor positive if estrogen receptor or progesterone receptor expression was 10% or higher according to IHC, as per European guidelines. 17 corresponded to an IHC score of 0, whereas an ERBB2-low score corresponded to an IHC score of 1+ or 2+ with negative FISH or CISH findings.

Objectives and End Points
The primary objective of the present study was to compare the overall survival (OS) of patients with ERBB2-low MBC with that of patients with ERBB2-zero MBC in the overall population and in the hormone receptor-positive and hormone receptor-negative population subtypes. The secondary objectives were to compare progression-free survival under first-line treatments (PFS1) between these groups and to describe the patterns of treatment and evolution of the ERBB2 status between early disease and metastatic disease, if available. OS was the primary end point, defined as the delay between metastatic diagnosis and death from any cause. PFS1 was defined as the time between the starting date of first-line treatment and the date of first disease progression or date of death. The main method for handling missing time-to-event data was censoring. Patients who were still alive and without progression at the time of the analysis were censored at their last follow-up. A treatment line was defined as a given therapeutic strategy that was set up until disease progression or death; therefore, it may have involved multiple treatments, including chemotherapy, targeted agents, or endocrine therapy. De novo metastatic disease was defined as the presence of metastasis at the time or within 6 months (180 days) from the primary tumor diagnosis. Disease progression was defined as the appearance of a new metastatic site or progression of pre-existing metastases at least 1 month after the start of treatment.

Statistical Analysis
The data analysis was conducted from July 16, 2020, to April 1, 2022. Demographic characteristics, clinicopathological characteristics, and first-line treatment modalities of ERBB2-low MBC are presented for the overall population and by ERBB2 and hormone receptor status using commonly used statistics. Continuous variables were summarized using the median, minimum, maximum, and number of missing data. Qualitative variables have been summarized for the overall population and by IHC subgroups using counts, percentages, and the number of missing data. Differences between groups were assessed using a χ 2 or Fisher exact test for qualitative variables and Kruskal-Wallis test for continuous variables. The Kaplan-Meier method was used to estimate survival rates and median survival times in the overall population and by groups. Comparisons of ERBB2-low and ERBB2-zero MBC were performed using a 2-sided log-rank test. Univariable analysis was performed to identify the risk factors associated with OS and PFS1. Multivariable analysis was performed using a Cox proportional hazards model to evaluate the association between ERBB2 expression and OS or PFS1 adjusting for risk factors. Subgroups analyses were performed by hormone receptor status and treatment types. All statistical tests were 2-sided, and P < .05 was considered significant. Statistical analyses were performed using Stata statistical software version 16 (StataCorp).        Figure 2B).    (Figure 3). In univariate analyses, the median OS rate was similar between the groups for patients treated with frontline endocrine therapy.    (Figure 3).

Evolution of Low ERBB2 Expression Between Early and Advanced-Stage BC
ERBB2 status was determined for the metastatic tissue in 1423 cases (9.5%) and for the primary tumor (when no biopsy of metastatic tissue was performed) in 13 631 cases (90.5%) (Figure 4) 18,19 The discrepancy in ERBB2 expression between primary and metastatic disease may result from genetic drift during tumor progression, 20 intratumoral heterogeneity, 21 and selective pressure of therapies with potential upregulation of ERBB2 expression. 22,23 This instability is important to consider if dedicated drugs are approved in the near future.
Previous reports show inconsistent data regarding the specific characteristics of ERBB2-low BC and whether this is a distinct biological entity. In the hormone receptor-positive BC group, ERBB2-low expression was 33.0% in our study and approximately the same in previous reports. 24 We did not notice any difference in terms of age, tumor grade, and number or type of metastases.
However, the proportion of de novo metastatic diseases was higher in the ERBB2-low population.
Considering a biological point of view, a recent report by Schettini et al 14 13 Despite the high frequency of brain metastases in patients with ERBB2-positive MBC, 25 no difference in brain metastasis frequency was noticed in our series according to ERBB2 expression.  15 On the other hand, other studies have failed to demonstrate any impact of ERBB2-low status in a metastatic setting. 14,16,26 In early BC, a study 12 enrolling 2310 patients with ERBB2-zero early BCs from neoadjuvant trials showed that patients with ERBB2-low BC had a lower pathological complete response to neoadjuvant chemotherapy compared with patients with ERBB2-zero tumors (29.2% vs 39.0%; P < .001) suggesting lower chemosensitivity. 12 However, patients with ERBB2-low tumors had better OS (adjusted HR, 0.64; 95% CI, 0.48-0.86; P = .003). 12 The growing interest in the ERBB2-low BC subgroup is associated with the rapid development of antibody-drug conjugates. 27 Trastuzumab-deruxtecan has shown impressive results compared with standard chemotherapy with an improvement in PFS (HR, 0.50; 95% CI, 0.40-0.63; P < .001) and OS (HR, 0.64; 95% CI, 0.49-0.84; P = .001). 28 These results confirm the opportunity of using