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Next-generation sequencing identifies potential novel therapeutic targets in Chinese HGSOC patients
Junyan Tao1, Dantong Sun1, Hai Zhou1
1Precision Medicine Center of Oncology, The Affiliated Hospital of Qingdao University, Qingdao 266000, 59 Haier Road, Shandong 266000, China.
Background:
Targeted therapy, especially the use of poly (adenosine diphosphate ribose) polymerase (PARP) inhibitors (PARPis), has improved the outcome of patients with ovarian cancer. However, most high-grade serous ovarian cancer (HGSOC) patients have wild-type BRCA1/2, and it is necessary to disclose more potential novel targets for other available targeted drugs. So, detection of genetic alterations beyond BRCA1/2 is critical to screen HGSOC patients for personalized therapy. In this study, a broad, hybrid capture-based next-generation sequencing (NGS) assay was used to identify actionable genetic alterations from HGSOC cancer tissues.
Methods:
Sixty-eight patients with HGSOC were enrolled, including 6 International Federation of Gynecology and Obstetrics (FIGO) stage I, 15 stage II, 37 stage III and 10 stage IV patients. All patients signed informed consent forms. Potentially actionable genetic alterations, including base substitutions, indels, copy number alterations, and gene fusions, were identified using targeted NGS.
Results:
In our study, 14.7% (10/68) of the tumors harbored actionable genetic alterations in patients with BRCA1. A total of 25.0% (17/68) of patients without BRCA1 mutations harbored other actionable genetic alterations, such as homologous recombination repair (HRR) pathway-related genes (ATM, CDK12, FANCA, and FANCD2), PI3K/AKT/mTOR pathway genes (NF1, FBXW7, PIK3CA, PTEN, TSC1, and TSC2), and some other genes (ARID1A, FGFR1, KRAS, and NRAS). Furthermore, some patients harboring ARID1A or NF1 actionable genetic alterations showed good clinical efficacy to immune checkpoint inhibitors (ICIs) and everolimus, respectively.
Conclusions:
Our research indicates that 39.7% (27/68) of patients with HGSOC harbored at least one actionable genetic alteration. 25.0% (17/68) of patients had somatic mutations or copy number variations beyond BRCA1 mutations and might be treated with off-label therapy or to be allocated into clinical trial. NGS assays of HGSOC patients are necessary to screen actionable genetic alterations to guide personalized and precise treatment.
Insights
Nearly 40% of high-grade serous ovarian cancer patients have actionable genetic alterations beyond BRCA1. Next-generation sequencing (NGS) can identify these targets for personalized therapy, improving patient outcomes.
Area of Science:
- Oncology
- Genomics
- Precision Medicine
Background:
- Targeted therapies, including poly (adenosine diphosphate ribose) polymerase (PARP) inhibitors, have improved ovarian cancer treatment.
- Most high-grade serous ovarian cancer (HGSOC) patients lack BRCA1/2 mutations, necessitating identification of novel therapeutic targets.
- Genetic alterations beyond BRCA1/2 are critical for selecting HGSOC patients for personalized therapy.
Purpose of the Study:
- To identify actionable genetic alterations in HGSOC using next-generation sequencing (NGS).
- To assess the frequency of genetic alterations beyond BRCA1/2 in HGSOC.
- To guide personalized treatment strategies for HGSOC patients.
Main Methods:
- A hybrid capture-based NGS assay was employed to analyze HGSOC tumor tissues.
- Sixty-eight HGSOC patients across various FIGO stages were enrolled.
- Actionable genetic alterations, including base substitutions, indels, copy number alterations, and gene fusions, were identified.
Main Results:
- Actionable genetic alterations were found in 14.7% of patients with BRCA1 mutations.
- An additional 25.0% of patients without BRCA1 mutations had other actionable alterations in genes like ATM, CDK12, NF1, and ARID1A.
- Some patients with ARID1A or NF1 alterations responded well to immune checkpoint inhibitors or everolimus.
Conclusions:
- Nearly 40% (39.7%) of HGSOC patients harbor at least one actionable genetic alteration.
- A significant proportion (25.0%) of patients have actionable mutations beyond BRCA1, suitable for off-label therapy or clinical trials.
- NGS screening for actionable genetic alterations is essential for guiding personalized and precise HGSOC treatment.
