In:
Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 35, No. 15_suppl ( 2017-05-20), p. 5512-5512
Abstract:
5512 Background: Defective homologous recombination DNA repair (HRD) is associated with high grade serous (OC-S) histology, longer survival, and platinum (Pt) or PARP inhibitor (PARPi) sensitivity. HRD causes LOH, a pattern of allelic imbalance detectable by CGP. BRCAwt OC-S can have LOH and respond to PARPi, while non-serous (OC-NS) or difficult to classify (OC-NOS) OC are often less responsive to Pt-based therapy. Integrating multiple genomic features derived from CGP may define other therapeutically relevant subsets. Methods: DNA from FFPE tumor tissue obtained during clinical care for 4114 advanced OC was analyzed for all classes of genomic alterations (GA) by hybrid-capture, next-generation sequencing of up to 315 genes. Tumor subtype counts were OC-S, n = 2770; OC-NOS, n = 807; OC-NS, n = 537 (mucinous, clear cell, endometrioid, neuroendocrine, carcinosarcomas, and low grade serous). Algorithms evaluated microsatellite instability (MSI), tumor mutation burden (TMB; TMB-H ≥ 10 muts/Mb), and LOH (LOH-H ≥ 14, LOH-L 〈 14). Results: 706/4114 (17.2%) OC had ≥1 deleterious BRCA GA, OC-S (18.7%) more so than OC-NS (4.4%). Median LOH score for OC-S was significantly higher than OC-NS (12.8 vs. 5.8, p 〈 0.05). BRCAmut OC-S and OC-NS were similarly LOH-H (86% and 75%), unlike BRCAwt OC-S (38.4%) or OC-NS (18%). Regardless of LOH, similar co-occurrence of MYC (26.9%) and/or NF1 (19%) GA was seen in BRCAmut OC. BRCAwt LOH-L OC commonly had CCNE1 (19.7%), KRAS (19%), PIK3CA (16.2%), AKT2 (7.4%), ERBB2 (4.7%), or BRAF(3.3%) GA. Frequency of TMB-H was 2.5% and MSI-H 1%. Correlation of GA with treatment, clinical histories and outcomes for some patients will be presented. Conclusions: BRCAmut or OC-S are commonly LOH-H; ~1 in 5 BRCAwt OC-NS, including carcinosarcomas and mucinous, are also LOH-H. Genes co-mutated in late stage LOH-H OC may be linked to treatment resistance. CGP of this large OC cohort reveals molecular, rather than histologic, patient subsets that may benefit from PARPi (46.2% BRCAmut or LOH-H), targeted therapy ( 〉 50% BRCAwt LOH-L, excluding TP53) or immunotherapy (3.5% TMB-H or MSI-H), providing more support for insurance coverage and integration into OC clinical trials.
Type of Medium:
Online Resource
ISSN:
0732-183X
,
1527-7755
DOI:
10.1200/JCO.2017.35.15_suppl.5512
Language:
English
Publisher:
American Society of Clinical Oncology (ASCO)
Publication Date:
2017
detail.hit.zdb_id:
2005181-5
Permalink