Impact of neoadjuvant chemotherapy on somatic mutation status in high-grade serous ovarian carcinoma

Zibi Marchocki; Alicia Tone; Carl Virtanen; Richard de Borja; Blaise Clarke; Theodore Brown; Taymaa May

doi:10.1186/s13048-022-00983-5

Impact of neoadjuvant chemotherapy on somatic mutation status in high-grade serous ovarian carcinoma

J Ovarian Res. 2022 May 2;15(1):50. doi: 10.1186/s13048-022-00983-5.

Authors

Zibi Marchocki^{1

2}, Alicia Tone¹, Carl Virtanen³, Richard de Borja², Blaise Clarke⁴, Theodore Brown^{2

5}, Taymaa May^{6

7}

Affiliations

¹ Department of Surgical Oncology, Division of Gynecologic Oncology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
² Department of Obstetrics and Gynecology, University of Toronto, Toronto, ON, Canada.
³ Bioinformatics and HPC Services Core, Princess Margaret Cancer Centre, Toronto, Ontario, Canada.
⁴ Department of Pathology, University Health Network, Toronto, Ontario, Canada.
⁵ The Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
⁶ Department of Surgical Oncology, Division of Gynecologic Oncology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada. Taymaa.May@uhn.ca.
⁷ Department of Obstetrics and Gynecology, University of Toronto, Toronto, ON, Canada. Taymaa.May@uhn.ca.

Abstract

Background: Patients treated with neoadjuvant chemotherapy (NACT) for advanced high-grade serous ovarian carcinoma (HGSC) have a higher rate and shorter time to platinum-resistant recurrence compared to patients treated with primary cytoreductive surgery (PCS) and adjuvant chemotherapy. The purpose of this study is to determine the impact of NACT on somatic mutation status in platinum-sensitive and resistant HGSC. Patients with advanced HGSC who had a documented response to platinum-based NACT, a banked blood sample, and a banked tumor sample before and after NACT were identified. Whole exome and/or targeted deep sequencing was performed in matched normal and pre/post-NACT tumor samples from 3 platinum-resistant and 2 platinum-sensitive patients to identify somatic non-synonymous mutations at each time point.

Results: When comparing exonic non-synonymous mutations in pre-NACT and post-NACT samples from the same patient, an average of 41% (1-68%) of genes were mutated at both time points. There were no trends detected in the mutational burden following exposure to NACT in platinum-resistant vs. platinum-sensitive cases. The majority of mutated genes were unique to each case. We identified several genes that were commonly mutated in pre-NACT samples specific to platinum-resistant (CSPG4, SLC35G5, TUBA3D) or sensitive (CYP2D6, NUTM1, DNAH5) cases. Four mutated genes emerged exclusively in the platinum-resistant cases (ADGRV1, MUC17, MUC20, PAK2) following NACT.

Conclusions: Patients with advanced HGSC present with significant intra-tumor heterogeneity. NACT significantly impacts the somatic mutation status irrespective of the time to recurrence. The mutated genes detected in chemo-naive pre-NACT tumor samples from either resistant or sensitive cases could potentially have a role in the prediction of chemotherapy response in patients scheduled to receive NACT; larger studies are required to further validate these genes.

Keywords: High-grade serous ovarian cancer; Neoadjuvant chemotherapy; Non-synonymous gene mutation; Platinum resistance.

MeSH terms

Cystadenocarcinoma, Serous* / drug therapy
Cystadenocarcinoma, Serous* / genetics
Cystadenocarcinoma, Serous* / pathology
Female
Humans
Mutation
Neoadjuvant Therapy
Neoplasms, Glandular and Epithelial*
Ovarian Neoplasms* / drug therapy
Ovarian Neoplasms* / genetics
Ovarian Neoplasms* / pathology