Abstract
Background: The correlation of ERBB2 copy number gain (CNG) from tissue or circulating tumor DNA (ctDNA) by next-generation sequencing (NGS) with standard HER2 tissue evaluation is not well understood.Materials and Methods: We retrospectively identified patients with ERBB2 CNG on commercial NGS. We described their clinical-pathologic features and calculated the positive predictive value (PPV) of ERBB2 CNG by NGS for HER2-positivity by IHC and FISH testing.Results: 176 patients had NGS revealing an ERBB2 CNG (112 by tumor tissue and 91 by ctDNA). The cancer subtypes with the most cases with ERBB2 CNG by NGS were breast (n = 67), non-small cell lung (n = 25), colorectal (n = 18), gastroesophageal (n = 17), pancreatic (n = 11), and uterine (n = 11). The PPV of ERBB2 CNG in determining HER2 positivity by standard IHC/FISH definitions was 88% for tissue NGS (n = 57) and 80% for ctDNA (n = 47). The PPV among breast cancer patients for tissue NGS was 97% (n = 35) and ctDNA was 93% (n = 39). However, for non-breast cancer cases, the PPV of ERBB2 amplification by tissue NGS dropped to 76% (n = 22) and by ctDNA to 44% (n = 7).Conclusions: ERBB2 CNG by NGS is detected in numerous malignancies for which HER2 testing is not standard. Detection of ERBB2 CNG by tissue NGS and ctDNA has a high PPV for true HER2-positivity by standard IHC and/or FISH testing in breast cancer.
Highlights
Trastuzumab’s approval in 1998 after it was shown to improve overall survival in HER2-postive metastatic breast cancer is one of the earliest successes in precision oncology and targeted therapies [1]
177 patients were identified with copy number gain (CNG) of ERBB2 by tissue or blood-based next-generation sequencing (NGS) testing
ERBB2 CNG was seen in 18 subtypes of cancer (Figure 1), the most common malignancies of which were: breast (n = 68), non-small cell lung (NSCLC, n = 25), colorectal (n = 18), gastroesophageal (n = 17, 15 adenocarcinoma, 2 squamous), pancreatic (n = 11), uterine (n = 11), bladder/ upper tract (n = 7), ovarian/fallopian tube (n = 4), biliary (n = 3), and small cell lung cancers (SCLC, n = 3) (Figure 1)
Summary
Trastuzumab’s approval in 1998 after it was shown to improve overall survival in HER2-postive metastatic breast cancer is one of the earliest successes in precision oncology and targeted therapies [1]. Advances in next-generation sequencing (NGS) technology have translated into the ability to efficiently study a broad array of molecular changes in patients with advanced cancer [2]. Overexpression of HER2, primarily as a result of amplification of ERBB2, identifies an aggressive breast cancer phenotype with a high risk for metastatic disease to visceral organs and the central nervous system. HER2 overexpression and/or amplification is seen in other cancers and has been shown to be predictive of trastuzumab efficacy for these diseases [4,5,6]. The correlation of ERBB2 copy number gain (CNG) from tissue or circulating tumor DNA (ctDNA) by next-generation sequencing (NGS) with standard HER2 tissue evaluation is not well understood
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