GENOMIC LOSS OF HETEROZYGOSITY IN OVARIAN CANCER Trey
1 Keel ,
Bethany
2 Bustamante ,
and Marina
2 Frimer
1Donald
and Barbara Zucker School of Medicine at Hofstra/Northwell 2Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Northwell Health
Background Ovarian cancer in the United States is estimated to kill 13,940 people in 2020 (2.3% of all cancer deaths) and has a 5-year survival rate of just 48.6 percent, despite modern advancements in treatment.1 The mainstay of treatment includes the combination of surgical cytoreduction and systemic cytotoxic therapies. Investigation into the genetic basis of ovarian cancer can help inform future treatment paradigms for ovarian cancer. It is well known that BRCA1/2 deleterious mutations and other genetic alterations associated with homologous recombination deficiency (HRD) confer platinum sensitivity, as well as PARP inhibitor (PARPi) responsiveness. A contemporary phase III randomized control clinical trial of the PARPi olaparib in the frontline treatment of BRCA mutant ovarian cancer showed significant reduction in the risk of disease progression by 70%, hazard ratio (HR) 0.3.2 Genomic loss of heterozygosity (gLOH), the irreversible loss of one parental allele of a gene, is a marker of HRD. This retrospective chart review aims to assess for the correlation of specific genetic alterations found by next generation sequencing (NGS) and gLOH with clinical metrics: PARPi responsiveness, platinum sensitivity (PS), likelihood of optimal surgical cytoreduction, progression free survival (PFS) and overall survival (OS).
Hypothesis 1) We expect to find that tumors with high genomic loss of heterozygosity (gLOH-H) are associated with platinum sensitivity (PS) and PARPi responsiveness within this cohort. 2) We suspect there may be an association between gLOH, or a specific gene alteration (GA), with optimal tumor debulking at time of debulking surgery.
PARP Inhibitors in Normal Vs. BRCA Positive Cells Cells with a BRCA mutation
Normal Cells Base Excision Repair (PARP1)
Homologous Recombination (BRCA)
Consort Diagram
Base Excision Repair (PARP1)
Homologous Recombination (BRCA) BRCA Mutation
DNA Repair
DNA Repair
Cells with Drug Induced PARP1 inhibition Base Excision Repair (PARP1)
Homologous Recombination (BRCA)
PARPi
Cells with a BRCA mutation and PARP1 inhibition Base Excision Repair (PARP1)
Homologous Recombination (BRCA) BRCA Mutation
PARPi
DNA Repair
Cell Death
Methods This is a retrospective chart review comparing multiple clinical factors with next generation sequencing results of the tumor tissue in ovarian cancer patients treated at Northwell Health. Any patient with ovarian, fallopian tube (FT) or primary peritoneal cancer (PPC) that had next generation sequencing (NGS) testing was within our inclusion criteria. Patients were excluded if there was loss of follow up data in the medical record, primary site of disease was not ovary/FT/PPC, or if they did not meet quality control metrics for LOH testing on NGS panel. Relationships of GA, gLOH and PS, PARPi response and optimal cytoreduction were assessed using t-test or Wilcoxon rank-sum test for continuous variables, and Chisquare and Fisher’s exact test for categorical variables. Kaplan-Meier non-parametric product limit function was used to construct and estimate the recurrence free survival (RFS) and overall survival (OS) in the current dataset.
Results, Conclusions Final results and conclusions are pending. Statistical analysis is currently underway. We suspect there may be an association between genetic factors, optimal debulking at time of surgery, and clinical outcomes. Future directions will depend on final results.
Resources The Surveillance, Epidemiology, and End Results (SEER) Program. Cancer Stat Facts: Ovarian Cancer. The Surveillance, Epidemiology, and End Results (SEER) Program. Accessed September 26, 2020. www.seer.cancer.gov/statfacts/html/ovary.html Moore K, Colombo N, Scambia G, et al. Maintenance Olaparib in Patients with Newly Diagnosed Advanced Ovarian Cancer. New England Journal of Medicine. 2018;379(26):2495-2505. Swisher EM, McNeish IA, Coleman RL, et al. ARIEL 2/3: An integrated clinical trial program to assess activity of rucaparib in ovarian cancer and to identify tumor molecular characteristics predictive of response. Journal of Clinical Oncology. 2014;32(15_suppl):TPS5619-TPS5619. Coleman RL, Oza AM, Lorusso D, et al. Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial [published correction appears in Lancet. 2017 Oct 28;390(10106):1948]. Lancet. 2017;390(10106):1949-1961. doi:10.1016/S0140-6736(17)32440-6