KIT/PDGFRA/KDR amplification defines a novel molecular subtype of adenoid cystic carcinoma patients who may benefit from treatment with tyrosine kinase inhibitors.

BACKGROUND: Adenoid cystic carcinoma (ACC) is a rare cancer with an aggressive phenotype and the high incidence of recurrence and distant metastasis severely affects the overall survival of ACC patients. Understanding the molecular mechanisms that drives ACC could improve the treatment and outcomes of patients with this disease. METHODS: Actionable genetic alterations in 52 surgically resected ACC tissue samples were identified using targeted next generation sequencing (NGS). Expression of c-KIT/PDGFRα/VEGFR2 was assessed by immunohistochemistry (IHC). Sunitinib, a multi-targeted small molecule inhibitor of receptor tyrosine kinases (RTKs), was used off-label in one ACC patient harboring the KIT/PDGFRA/KDR amplification. RESULTS: Potentially actionable genetic alterations were detected in 61.5% (32/52) of patients. In addition to the common actionable targets identified in NOTCH signaling and FGF/PI3K pathway, multiple novel gene fusions were detected in 7.7% (4/52) of ACC patients. Specifically, the KIT/PDGFRA/KDR amplification was identified in 2 of 52 (3.8%) cases and triple positive c-KIT/PDGFRα/VEGFR2 by IHC was associated with a significantly higher likelihood of distant metastasis. Furthermore, an advanced ACC patient with the KIT/PDGFRA/KDR amplification and who was positive for three encoded proteins showed a partial response to sunitinib. CONCLUSIONS: A total of 61.5% of ACC patients were found to harbor at least one actionable genetic alteration via a targeted NGS in this study. The KIT/PDGFRA/KDR amplification as well as triple positive c-KIT/PDGFRα/VEGFR2 defined a distinctive molecular phenotype that was characterized by distant metastasis. Clinical trials investigating the application of RTKs in ACC patients with the KIT/PDGFRA/KDR amplification or triple positive c-KIT/PDGFRα/VEGFR2 are warranted.

Landscape of Actionable Genetic Alterations Profiled from 1,071 Tumor Samples in Korean Cancer Patients.

PURPOSE: With the emergence of next-generation sequencing (NGS) technology, profiling a wide range of genomic alterations has become a possibility resulting in improved implementation of targeted cancer therapy. In Asian populations, the prevalence and spectrum of clinically actionable genetic alterations has not yet been determined because of a lack of studies examining high-throughput cancer genomic data. MATERIALS AND METHODS: To address this issue, 1,071 tumor samples were collected from five major cancer institutes in Korea and analyzed using targeted NGS at a centralized laboratory. Samples were either fresh frozen or formalin-fixed, paraffin embedded (FFPE) and the quality and yield of extracted genomic DNA was assessed. In order to estimate the effect of sample condition on the quality of sequencing results, tissue preparation method, specimen type (resected or biopsied) and tissue storage time were compared. RESULTS: We detected 7,360 non-synonymous point mutations, 1,164 small insertions and deletions, 3,173 copy number alterations, and 462 structural variants. Fifty-four percent of tumors had one or more clinically relevant genetic mutation. The distribution of actionable variants was variable among different genes. Fresh frozen tissues, surgically resected specimens, and recently obtained specimens generated superior sequencing results over FFPE tissues, biopsied specimens, and tissues with long storage duration. CONCLUSION: In order to overcome, challenges involved in bringing NGS testing into routine clinical use, a centralized laboratory model was designed that could improve the NGS workflows, provide appropriate turnaround times and control costs with goal of enabling precision medicine.

Landscape of Actionable Genetic Alterations Profiled from 1,071 Tumor Samples in Korean Cancer Patients / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: With the emergence of next-generation sequencing (NGS) technology, profiling a wide range of genomic alterations has become a possibility resulting in improved implementation of targeted cancer therapy. In Asian populations, the prevalence and spectrum of clinically actionable genetic alterations has not yet been determined because of a lack of studies examining high-throughput cancer genomic data. MATERIALS AND METHODS: To address this issue, 1,071 tumor samples were collected from five major cancer institutes in Korea and analyzed using targeted NGS at a centralized laboratory. Samples were either fresh frozen or formalin-fixed, paraffin embedded (FFPE) and the quality and yield of extracted genomic DNA was assessed. In order to estimate the effect of sample condition on the quality of sequencing results, tissue preparation method, specimen type (resected or biopsied) and tissue storage time were compared. RESULTS: We detected 7,360 non-synonymous point mutations, 1,164 small insertions and deletions, 3,173 copy number alterations, and 462 structural variants. Fifty-four percent of tumors had one or more clinically relevant genetic mutation. The distribution of actionable variants was variable among different genes. Fresh frozen tissues, surgically resected specimens, and recently obtained specimens generated superior sequencing results over FFPE tissues, biopsied specimens, and tissues with long storage duration. CONCLUSION: In order to overcome, challenges involved in bringing NGS testing into routine clinical use, a centralized laboratory model was designed that could improve the NGS workflows, provide appropriate turnaround times and control costs with goal of enabling precision medicine.