Clinical relevance and concordance of HER2 status in local and central testing—an analysis of 1581 HER2-positive breast carcinomas over 12 years

Abstract

Human epidermal growth factor receptor 2 (HER2) is a central predictive biomarker in breast cancer. Inaccurate HER2 results in different laboratories could be as high as 20%. However, this statement is based on data generated more than 13 years ago and may not reflect the standards of modern diagnostic pathology. We compared central and local HER2 testing in a total of 1581 HER2-positive tumors from five clinical trials. We evaluated the clinical relevance for pathological complete response (pCR) and disease-free survival in a subgroup of 677 tumors, which received an anti-HER2 therapy. Over the period of 12 years, the discordance rate for HER2 decreased from 52.4 (GeparTrio) to 8.4% (GeparSepto). Discordance rates were significantly higher in hormone receptor (HR)-positive tumors (26.6%), compared to HR-negative tumors (16.3%, P<0.0001), which could be explained by a different distribution of HER2 mRNA levels in HR-positive and HR-negative tumors. pCR rates were significantly lower in discordant tumors (13.7%) compared to concordant tumors (32.2%, GeparQuattro and GeparQuinto, P<0.001). In survival analysis, tumors with discordant HER2 testing had a reduced overall survival (OS) in the HR-negative group (P=0.019) and a trend for improved OS in the HR-positive group (P=0.125). The performance of local HER2 testing was considerably improved over time and has reached a 92% concordance, which shows that quality initiatives in diagnostic pathology are working. Tumors with discordant HER2 testing had a reduced therapy response and different survival rates.

Estrogen, progesterone, and human epidermal growth factor receptor 2 discordance between primary and metastatic breast cancer

“…Several studies reported varying concordance of results between the surgical specimen and core needle biopsy of ER (77.8 to 99%), PR (69 to 97%), and HER2 (64 to 97%), respectively, with particular emphasis placed on a general tendency for higher discrepancies in PR status [22][23][24][25][26][27]. In addition to substantial improvement in receptor measurement accuracy, interlaboratory variation still exists in the assignment of receptor status [28,29]. The choice of method (such as IHC and RT-PCR), the assay method (dual-antibody vs single-antibody ER assay), as well as sample processing (e.g., decalcification reduced staining intensity especially in bone metastasis) may yield to discordant results [29][30][31].…”

Local and Central Evaluation of HER2 Positivity and Clinical Outcome in Advanced Gastric and Gastroesophageal Cancer—Results from the AGMT GASTRIC-5 Registry

“…In locoregional breast cancer, discordant HER2 results were reported to be associated with lower pathological complete remission rates after neoadjuvant systemic therapy. However, the discordance rate between local and central HER2 testing has dramatically improved from 52% to 8% over a period of 12 years in breast cancer [29]. In the GASTRIC-5 registry we did not see a statistically significant learning effect of HER2 testing over time (Figure 2).…”

Tumor Infiltrating Lymphocytes and NHERF1 Impact on Prognosis of Breast Cancer Patients

“…There are recent evidences that support the role of immune-related factors in BC prognosis and treatment, and in particular, TILs represent a crucial factor in this scenario. Most of TNBCs and HER2-positive BCs have dense immune infiltrates, and some studies showed that the presence of TILs in tumor tissue may predict response to neoadjuvant therapy [10] and also may have a significant prognostic value after adjuvant chemotherapy [[11], [12], [13], [14]]. Although the concept of evaluating TILs in BC and making correlations with clinical outcome is not new, yet there are few consistent data to consider TILs as reliable prognostic factors because of same complex and controversial aspects [15].…”