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Testing Targeted Therapies in Cancer using Structural DNA Alteration Analysis and Patient-Derived Xenografts
Published on: July 25, 2020
Genetic alterations and their therapeutic implications in epithelial ovarian cancer
Nina Lapke1,2, Chien-Hung Chen1, Ting-Chang Chang3,4
1ACT Genomics, Co. Ltd., 3F., No.345, Xinhu 2nd Rd., Neihu Dist, Taipei City, 114, Taiwan.
Background:
Genetic alterations for epithelial ovarian cancer are insufficiently characterized. Previous studies are limited regarding included histologies, gene numbers, copy number variant (CNV) detection, and interpretation of pathway alteration patterns of individual patients.
Methods:
We sequenced 410 genes to analyze mutations and CNV of 82 ovarian carcinomas, including high-grade serous (n = 37), endometrioid (n = 22) and clear cell (n = 23) histologies. Eligibility for targeted therapy was determined for each patient by a pathway-based approach. The analysis covered DNA repair, receptor tyrosine kinase, PI3K/AKT/MTOR, RAS/MAPK, cell cycle, and hedgehog pathways, and included 14 drug targets.
Results:
Postulated PARP, MTOR, and CDK4/6 inhibition sensitivity were most common. BRCA1/2 alterations, PTEN loss, and gain of PIK3CA and CCND1 were characteristic for high-grade serous carcinomas. Mutations of ARID1A, PIK3CA, and KRAS, and ERBB2 gain were enriched in the other histologies. PTEN mutations and high tumor mutational burden were characteristic for endometrioid carcinomas. Drug target downstream alterations impaired actionability in all histologies, and many alterations would not have been discovered by key gene mutational analysis. Individual patients often had more than one actionable drug target.
Conclusions:
Genetic alterations in ovarian carcinomas are complex and differ among histologies. Our results aid the personalization of therapy and biomarker analysis for clinical studies, and indicate a high potential for combinations of targeted therapies.
Insights
Genetic alterations in ovarian cancer are complex and vary by histology. Understanding these genetic profiles can personalize treatment and improve outcomes for patients with ovarian carcinomas.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Epithelial ovarian cancer (EOC) genetic landscape remains incompletely understood.
- Previous research has limitations in histology inclusion, gene analysis scope, copy number variant (CNV) detection, and pathway-level interpretation.
- A comprehensive genetic characterization is needed for personalized therapeutic strategies.
Purpose of the Study:
- To comprehensively analyze genetic alterations, including mutations and CNVs, across different epithelial ovarian cancer histologies.
- To assess the actionability of identified genetic alterations for targeted therapy eligibility using a pathway-based approach.
- To explore the potential for combination targeted therapies in ovarian cancer.
Main Methods:
- Sequencing of 410 genes in 82 ovarian carcinomas (high-grade serous, endometrioid, clear cell histologies).
- Analysis of mutations and copy number variants (CNVs).
- Pathway-based assessment of targeted therapy eligibility, focusing on DNA repair, RTK, PI3K/AKT/MTOR, RAS/MAPK, cell cycle, and hedgehog pathways, including 14 drug targets.
Main Results:
- PARP, MTOR, and CDK4/6 inhibition sensitivity were frequently observed.
- Specific genetic alterations (e.g., BRCA1/2, PTEN loss, PIK3CA/CCND1 gain) were characteristic of high-grade serous carcinomas.
- Other histologies showed enrichment for mutations in ARID1A, PIK3CA, KRAS, and ERBB2 gain; endometrioid carcinomas were characterized by PTEN mutations and high tumor mutational burden.
- Actionability of targeted therapies was often limited by downstream alterations, and multiple actionable targets were common per patient.
- Key gene mutational analysis alone would miss numerous actionable alterations.
Conclusions:
- Ovarian carcinoma genetic alterations are intricate and histologically dependent.
- Findings support personalized therapy selection and biomarker development for clinical trials.
- There is significant potential for utilizing combination targeted therapies in ovarian cancer treatment.
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