Abstract A28: Intratumor heterogeneity and homologous recombination deficiency of high-grade serous ovarian cancer are associated with prognosis and molecular subtypes and change in treatment course
Authors: Takaya Hisamitsu , Nakai Hidekatsu , Murakami Kosuke , Matsumura Noriomi 
Published: September 2020

Abstract
Background: High-grade serous ovarian cancers (HGSOC) are genomically characterized by homologous recombination deficiency (HRD) and TP53 mutations, which lead to intratumor heterogeneity (ITH). High degree of loss of heterozygosity (LOH) indicates HRD, a characteristic associated with sensitivity to platinum agents and poly-(ADP ribose) polymerase (PARP) inhibitors. This study aimed to reveal the relationship between HRD, ITH, and prognosis and analyze their changes during treatment.
Methods: We obtained 573 single-nucleotide polymorphism (SNP) array and gene expression array data from The Cancer Genome Atlas. SNP array data were processed to calculate the Clonality Index (CI) and LOH scores. Gene expression array data were used for classifying molecular subtypes. Pathway analysis was performed by Ingenuity Pathway Analysis (IPA). Additionally, we obtained 33 samples from 20 HGSOC patients, including 4 samples from interval debulking surgery (IDS) and 9 samples from recurrent surgery. DNA extracted from FFPE specimens was analyzed with an OncoScan FFPE Assay Kit and the number of clones and the LOH score was calculated. GISTIC 2.0 was used to identify copy number aberrations in tumors.
Results: We divided HGSOC samples into 2 groups by the CI and LOH scores, respectively. The high CI group (CI≧3) showed statistically shorter disease-free survival (DFS) and progression-free survival (PFS), but there was no statistically significant difference about overall survival (OS) (p&lt;0.001, 0.01, p=0.419, respectively). The high LOH group (LOH score≧16) showed statistically longer DFS, PFS, and OS (p&lt;0.001, 0.01, 0.001, respectively). Combining the two factors, the high LOH/low CI group showed a statistically good prognosis. In terms of molecular subtypes, the mesenchymal subtype, which had a poor prognosis, showed a high CI with statistically significant difference (p=0.0403) and the immunoreactive subtype, which had a good prognosis, showed a tendency to have a high LOH score (p=0.0762). With IPA analysis, it was predicted that the activation, migration, and adhesion of immune cells were activated in the high LOH group and high LOH/low CI group. Throughout treatment, the CI at primary surgery was 3 in 3 cases and 2 in 1 case, and at IDS, the CI decreased to 1 in all 4 cases, and then the CI increased at the secondary surgery in all 3 recurrent cases. The LOH score did not change in 2 cases and greatly decreased in 2 cases from primary surgery to IDS and then increased at secondary surgery. With GISTIC analysis, a pattern of the copy number variant compared between primary and recurrent surgery had few differences, but amplification of 8q24 was found at IDS with statistical significance.
Conclusions: ITH and HRD were associated with prognosis in HGSOC. ITH of remaining tumors at IDS decreased compared with that of primary tumors. This study indicated that it is important to analyze tumors that remain after chemotherapy for investigating the mechanism of the development of chemoresistance.
Citation Format: Hisamitsu Takaya, Hidekatsu Nakai, Kosuke Murakami, Noriomi Matsumura. Intratumor heterogeneity and homologous recombination deficiency of high-grade serous ovarian cancer are associated with prognosis and molecular subtypes and change in treatment course [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr A28.