Retrospective study to estimate the prevalence of HER2-low breast cancer (BC) and describe its clinicopathological characteristics.

Abstract

1087 Background: Approximately 50% of BCs traditionally categorized as HER2 negative (HER2-neg) express low levels of HER2 (IHC 1+ or IHC 2+/ISH-; Miglietta, NPJ Breast Cancer 2021). HER2-targeted therapies for HER2-low metastatic BC (mBC) are under investigation (eg, T-DXd in the phase 3 DESTINY-Breast04 study; NCT03734029), but HER2 assays currently used to select patients (pts) for approved anti-HER2 therapies are optimized for high HER2 expression and are not validated for HER2-low detection. A recent study found relatively poor agreement (<70% interrater agreement) in evaluation of IHC scores of 0 and 1+ using current HER2 assays (Fernandez, JAMA Oncol 2022). Our objectives were to assess the prevalence of HER2-low among HER2-neg based on rescored HER2 IHC slides after training on low-end expression scoring and to describe pt characteristics of HER2-low vs HER2 IHC 0 mBC. Preliminary results are reported for 233 of 1000 planned pts. Methods: This multicenter, retrospective study (NCT04807595) included pts with confirmed HER2-neg unresectable/mBC diagnosed between 2015 and 2017. Local laboratories, blinded to historical HER2 scores, rescored HER2 IHC-stained slides. HER2 was assessed using Ventana 4B5 and other assays. BCs were categorized as HER2-low or HER2 IHC 0. The prevalence of HER2-low BC among pts originally scored as HER2-neg was measured. Demographics (eg, age, country, race) and clinicopathological characteristics were examined via medical charts/electronic health records. Concordance between historical HER2 scores and rescores was assessed. Results: HER2 rescores were obtained for 233 pts (mean age, 54 y). HER2-low prevalence was 63.2% overall and numerically greater in hormone receptor (HR)–positive vs HR-negative subgroups (66.1% vs 54.8%; Table). No notable differences in prevalence were seen among different HER2 assays or in demographic/baseline disease characteristics between the HER2-low and HER2 IHC 0 groups. Concordance rate between historical and rescored slides for HER2-status classification was 82.3%. The presentation will include an expanded data set (≈400 pts) with additional results. Conclusions: Data on HER2-low prevalence in BC is limited. Preliminary data from this study of mBC samples suggest a somewhat higher prevalence estimate (≈63%) than a previous study of primary BC samples (≈50%). Concordance was 82%; ongoing analyses with updated data will clarify the concordance between rescored and historical HER2 slides. These data can support development of best practices for identifying pts with HER2-low expression who may benefit from HER2-targeted therapies. Clinical trial information: NCT04807595. [Table: see text]

The HER2-low revolution in breast oncology: steps forward and emerging challenges

“…Analyses of large retrospective cohorts of patients with BC often reported inconsistent findings and there is still no agreement in the field. 17 – 35 Most studies have identified no major difference in clinicopathologic characteristics nor prognosis for HER2-low expression, 24 , 30 , 31 , 36 few studies have instead suggested a better 29 , 32 or worse prognosis 25 associated with HER2-low BC ( Table 1 ). Of note, a positive correlation between estrogen receptor (ER) level and HER2-low expression has been reported, with approximately 60% of HR-positive/HER2-negative BC being HER2-low, compared with up to 40% of TNBC.…”

Diagnostic value of core needle biopsy for determining HER2 status in breast cancer, especially in the HER2-low population

“…Variations in staining of HER2-low cases led by different antibodies and kits should also be considered. A global multicenter study used different assays to re-interpret IHC results in traditionally defined HER2-negative patients and reported a HER2-low concordance of 85.1% in Ventana 4B5 assay, while 78.2% in non-Ventana 4B5 assay [ 31 ]. In another study, the HER2 status was assessed by Ventana 4B5 and HercepTest antibodies, showing the detection rate of HER2-low tumors was 27.4% and 9.2%, respectively [ 32 ].…”

An Overview of Clinical Development of Agents for Metastatic or Advanced Breast Cancer Without ERBB2 Amplification (HER2-Low)

“…However, a study of 389 patients found no significant differences in patient demographics or clinical char-acteristics between patients with ERBB2-low and those with ERBB2zero mBC. 17 The prevalence of tumor subtypes may depend on HR status. In a study of 3689 patients with ERBB2-negative breast cancer, 20 58.9% of HR-positive, ERBB2-low tumors were luminal A, 33.4% were luminal B, 3.0% were ERBB2-enriched, 1.9% were basal-like, and 2.8% were normal-like using the PAM50 intrinsic subtype classification.…”

“…Reports on the prognostic significance of ERBB2-low have been mixed. Although several studies have found no significant differences in outcomes or clinical characteristics between patients with ERBB2-low and ERBB2-zero breast cancer, 13,15,17,20 others have found ERBB2-low to have prognostic significance-particularly when considering other variables (Table 2). 7,14,21 In 2 studies, lower pathological complete response (pCR) rates were reported for ERBB2-low than for ERBB2-zero tumors, 7,28 which is consistent with the lower proliferation status (based on expression of Ki-67 and other proliferation-related genes) in ERBB2-low compared with ERBB2-zero tumors, Ki-67 being predictive of pCR.…”