Abstract 2240: A case series of ERBB2 indel driver mutations in non-small cell lung cancer identified by cell-free circulating tumor DNA NGS

Abstract

Abstract Background: In-frame insertions between codons 775 and 881 in exon 20 of the ERBB2 gene, of which a 12 base pair YVMA insertion is the most common, are activating mutations in 2%-4% of non-small cell lung cancers (NSCLC), and have also been reported in exon 19 and 20 in breast cancer. These driver mutations are not captured with IHC or FISH staining because in the majority of cases, the ERBB2 gene is not amplified and HER2 protein is not overexpressed. Next generation sequencing (NGS) of circulating cell-free DNA (cfDNA) provides a non-invasive means of identifying these potential driver mutations. Method: Guardant360TM is a targeted cfDNA NGS panel using hybrid capture and complete exon sequencing for single nucleotide variant detection in 70 genes, copy number amplifications (CNA) in 16 genes, and fusions in six genes and indels in EGFR, ERBB2 and MET exon 14 skipping. De-identified pathology and genotyping reports were reviewed for consecutive patients in which ERBB2 indels were identified in clinical practice. Results: Guardant360 identified ERBB2 indels in 27 of 2,093 (1.3%) of non-squamous NSCLC cases, with a single concomitant ERBB2 gene amplification. For this ERBB2 indel series, pathology reports revealed no patients with HER2 amplification via IHC or FISH, nor ERBB2 point mutation via NGS, but were only available in 25% of cases. Eight of the ERBB2 indels were confirmed by tissue NGS reports with zero false positives (100% PPV). 80% of ERBB2 indels were the common p.Tyr772_Ala775dup (YVMA insertion) in exon 20 followed by other insertions in codons 772 through 814. A single ERBB2 exon 20 p.Leu755_Glu757delinsProLys net deletion at 3.9% mutant allele fration (MAF) was noted in one patient, for whom outcome data was available. Initial tissue was IHC negative for HER2 overexpression at the referring hospital where the archival tissue biopsy was exhausted and so could not be sequenced. Based on the cfDNA finding of ERBB2 indel, the patient was switched from cytotoxic chemotherapy to trastuzumab with objective response on PET/CT and a repeat Guardant360 showed the ERBB2 indel MAF had dropped below the test limit of detection. After four months the patient progressed and it was decided to switch to ado-emtansine trastuzumab (T-DM1) in late November. Results: ERBB2 indels can be identified without tissue in NSCLC patients with 100% PPV in this modest cfDNA series. In a patient whose tissue was not available for sequencing, an objective response with trastuzumab was obtained. Citation Format: Nir Peled, Anna Belilovski-Rozenblum, Lior Soussan-Gutman, Christine Lee, AmirAli Talasaz, Richard B. Lanman. A case series of ERBB2 indel driver mutations in non-small cell lung cancer identified by cell-free circulating tumor DNA NGS. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2240.