HER2-low expression in patients with advanced or metastatic solid tumors

Abstract

Background: Human epidermal growth factor receptor 2 (HER2)-low is a newly defined category with HER2 1+ or 2+ expression by immunohistochemistry (IHC) and lack of HER2 gene amplification measured by in situ hybridization (ISH). Much remains unknown about the HER2-low status across tumor types and changes in HER2 status between primary and metastatic samples.

Patients and methods: HER2 expression by IHC was evaluated in 4701 patients with solid tumors. We have evaluated the HER2 expression by IHC and amplification by ISH in paired breast and gastric/gastroesophageal (GEJ) primary and metastatic samples. HER2 expression was correlated with ERBB2 genomic alterations evaluated by next-generation sequencing (NGS) in non-breast, non-gastric/GEJ samples.

Results: HER2 expression (HER2 IHC 1-3+) was found in half (49.8%) of the cancers, with HER2-low (1 or 2+) found in many tumor types: 47.1% in breast, 34.6% in gastric/GEJ, 50.0% in salivary gland, 46.9% in lung, 46.5% in endometrial, 46% in urothelial, and 45.5% of gallbladder cancers. The concordance evaluation of HER2 expression between primary and metastatic breast cancer samples showed that HER2 3+ remained unchanged in 87.1% with a strong agreement between primary and metastatic samples, with a weighted kappa (Κ) of 0.85 (95% confidence interval 0.79-0.91). ERBB2 alterations were identified in 117 (7.5%) patients with non-breast, non-gastric/GEJ solid tumors who had NGS testing. Of 1436 patients without ERBB2 alterations, 512 (35.7%) showed any level HER2 expression by IHC.

Conclusion: Our results show that HER2-low expression is frequently found across tumor types. These findings suggest that many patients with HER2-low solid tumors might benefit from HER2-targeted therapies.

Keywords: ERBB2 amplification; HER2 amplification; HER2 expression; HER2-low; targeted therapy.

Figure 1.. Distribution of HER2 IHC expression levels across cancers.

Histologies with ≥10 patients have been included in the graph. Refer to Table 1 for more detailed information. CCA, cholangiocarcinoma; CUP, cancer of unknown primary; FT, fallopian tube cancer; GEJ, gastroesophageal; HCC, hepatocellular carcinoma; HER2, human epidermal growth factor receptor 2; HN-ACC, head and neck-adenoid cystic carcinoma; HN, head and neck; HNSCC, head and neck squamous cell carcinoma.

Figure 2.. Distribution of HER2 expression levels evaluated in metastatic samples of stage-IV breast and gastric/ GEJ cancer patients.

(A) Pie chart showing the distribution of HER2 IHC expression levels in the breast cohort (n = 867). (B) Bar plot showing the distribution of HER2 ISH levels for evaluable breast cases. (C) Pie chart showing the distribution of HER2 IHC expression levels in the gastric/GEJ cohort (n = 48). (D) Bar plot showing the distribution of HER2 ISH levels for evaluable gastric/GEJ cases. (E) Bar plot showing the distribution of HER2 expression levels in the breast (n = 850) and gastric/GEJ (n = 44) cohorts. HER2 expression levels were defined as: HER2-negative = HER2 IHC 0, HER2-low = HER2 IHC 1+ or 2+, and ISH: Non-amplified, HER2-positive = HER2 IHC 3+ and/or ISH: Amplified (Please refer to the Methods section for more detailed information). GEJ, gastroesophageal; HER2, human epidermal growth factor receptor 2; IHC, immunohistochemistry; ISH, in situ hybridization.

Figure 3.. Comparison of HER2 expression levels in paired primary and metastasis samples of patients with metastatic breast and gastric/ GEJ cancer.

Flow diagrams and complementary tables showing the evolution of HER2 expression from primary to metastatic (A) breast (n = 640) and (B) gastric/GEJ (n = 25) cancers. HER2 expression levels were defined as: HER2-negative = HER2 IHC 0, HER2-low = HER2 IHC 1+ or 2+, and ISH: Non-amplified, HER2-positive = HER2 IHC 3+ and/or ISH: Amplified (Please refer to the Methods section for more detailed information). Row percentages have been used in the construction of tables. GEJ, gastroesophageal; HER2, human epidermal growth factor receptor 2; IHC, immunohistochemistry; ISH, in situ hybridization; NGS, next-generation sequencing.

Figure 4.. Distribution of HER2 IHC expression levels by ERBB2 alterations in patients with non-breast, non-gastric/ GEJ histologies.

(A) Flow diagram of the ERBB2 alteration co-occurrence study. (B) Bar plot shows distribution of HER2 IHC expression levels by ERBB2 alterations identified by tissue- and/or cfDNA-based NGS testing using a panel that includes ERBB2 in patients with non-breast, non-gastric/GEJ histologies (n = 1553). Please refer to Supplementary Table S3, available at https://doi.org/10.1016/j.annonc.2023.08.005, for more detailed information on patients with ERBB2 alterations. Panels (C) and (D) show the distribution of HER2 IHC scores in non-breast, non-gastric/GEJ patients with ERBB2 alterations identified by tissue-based (n = 85) and cfDNA-based (n = 32) NGS testing, respectively. Please refer to Supplementary Table S4, available at https://doi.org/10.1016/j.annonc.2023.08.005, for more detailed information. cfDNA, circulating free DNA; GEJ, gastroesophageal; HER2, human epidermal growth factor receptor 2; IHC, immunohistochemistry; NGS, next-generation sequencing.