Gut microbiome associated with PARP inhibitor efficacy in patients with ovarian cancer

Mika Okazawa-Sakai; Shunsuke A Sakai; Ichinosuke Hyodo; Satoshi Horasawa; Kentaro Sawada; Takao Fujisawa; Yasuko Yamamoto; Shogen Boku; Yoh Hayasaki; Masanori Isobe; Daisuke Shintani; Kosei Hasegawa; Tomomi Egawa-Takata; Kimihiko Ito; Kei Ihira; Hidemichi Watari; Kazuhiro Takehara; Hiroshi Yagi; Kiyoko Kato; Tatsuyuki Chiyoda; Kenichi Harano; Yoshiaki Nakamura; Riu Yamashita; Takayuki Yoshino; Daisuke Aoki

doi:10.3802/jgo.2025.36.e38

Gut microbiome associated with PARP inhibitor efficacy in patients with ovarian cancer

J Gynecol Oncol. 2024 Oct 21. doi: 10.3802/jgo.2025.36.e38. Online ahead of print.

Authors

Mika Okazawa-Sakai^#^{1

2}, Shunsuke A Sakai^#^{3

4}, Ichinosuke Hyodo⁵, Satoshi Horasawa⁶, Kentaro Sawada⁷, Takao Fujisawa^{6

8}, Yasuko Yamamoto⁹, Shogen Boku¹⁰, Yoh Hayasaki¹¹, Masanori Isobe¹¹, Daisuke Shintani¹², Kosei Hasegawa¹², Tomomi Egawa-Takata¹³, Kimihiko Ito¹³, Kei Ihira¹⁴, Hidemichi Watari¹⁴, Kazuhiro Takehara¹, Hiroshi Yagi¹⁵, Kiyoko Kato¹⁵, Tatsuyuki Chiyoda¹⁶, Kenichi Harano¹⁷, Yoshiaki Nakamura^{6

18

19}, Riu Yamashita^{4

20}, Takayuki Yoshino¹⁹, Daisuke Aoki^{16

21}

Affiliations

¹ Department of Gynecologic Oncology, NHO Shikoku Cancer Center, Matsuyama, Japan.
² Department of Cancer Genomic Medicine, NHO Shikoku Cancer Center, Matsuyama, Japan.
³ Department of Integrated Biosciences, Graduate School of Frontier Science, University of Tokyo, Kashiwa, Japan.
⁴ Division of Translational Informatics, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Japan.
⁵ Department of Gastrointestinal Medical Oncology, NHO Shikoku Cancer Center, Matsuyama, Japan.
⁶ Translational Research Support Office, National Cancer Center Hospital East, Kashiwa, Japan.
⁷ Department of Medical Oncology, Kushiro Rosai Hospital, Kushiro, Japan.
⁸ Department of Head and Neck Medical Oncology, National Cancer Center Hospital East, Kashiwa, Japan.
⁹ Department of Hereditary Tumors, NHO Shikoku Cancer Center, Matsuyama, Japan.
¹⁰ Cancer Treatment Center, Kansai Medical University Hospital, Hirakata, Japan.
¹¹ Department of Obstetrics and Gynecology, Gifu University Graduate School of Medicine, Gifu, Japan.
¹² Department of Gynecology Oncology, Saitama Medical University International Medical Center, Hidaka, Japan.
¹³ Department of Obstetrics and Gynecology, Kansai Rosai Hospital, Amagasaki, Japan.
¹⁴ Department of Obstetrics and Gynecology, Hokkaido University Hospital, Sapporo, Japan.
¹⁵ Department of Obstetrics and Gynecology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
¹⁶ Department of Obstetrics and Gynecology, Keio University School of Medicine, Tokyo, Japan.
¹⁷ Department of Medical Oncology, National Cancer Center Hospital East, Kashiwa, Japan.
¹⁸ International Research Promotion Office, National Cancer Center Hospital East, Kashiwa, Japan.
¹⁹ Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan.
²⁰ Department of Computational Biology and Medical Sciences, Graduate School of Frontier Science, University of Tokyo, Kashiwa, Japan.
²¹ International University of Health and Welfare Graduate School. [email protected].

^# Contributed equally.

PMID: 39453391
DOI: 10.3802/jgo.2025.36.e38

Abstract

Objective: To investigate an association between the gut microbiome and efficacy of poly(ADP-ribose) polymerase inhibitors (PARPi) in ovarian cancer.

Methods: This study conducted fecal microbiome analysis (16S rRNA gene sequencing) and circulating tumor DNA (ctDNA) profiling for ovarian cancer patients who underwent PARPi maintenance therapy. Fecal and blood samples were collected at the baseline and the progressive disease (PD) or last follow-up. The relative abundance of gut microbes and progression-free survival (PFS) were analyzed using linear discriminant analysis of effect size and the Cox proportional hazard model according to BRCA1/2 mutation (BRCA1/2mut) status detected by ctDNA sequencing.

Results: Baseline samples were available from 23 BRCA1/2mut-positive patients and 33 BRCA1/2mut-negative patients. The microbes enriched in the baseline samples with long PFS were Bifidobacterium, Roseburia, Dialister, Butyricicoccus, and Bilophila for BRCA1/2mut-positive patients and Phascolarctobacterium for BRCA1/2mut-negative patients. In multivariate analyses dividing patients by the median values of relative abundances, no bacteria were associated with PFS in BRCA1/2mut-positive patients, whereas high Phascolarctobacterium abundances (≥1.11%) was significantly associated with longer PFS in BRCA1/2mut-negative patients (median 14.0 vs. 5.9 months, hazard ratio=0.28; 95% confidence interval=0.11-0.69; p=0.014). In the last samples, the relative abundances of Phascolarctobacterium were significantly higher in patients without PD (n=5) than those with PD (n=15) (median 1.25% vs. 0.06%; p=0.016).

Conclusion: High fecal composition of Phascolarctobacterium was associated with prolonged PFS in patients with BRCA1/2mut-negative ovarian cancer receiving PARPi therapy. Our results would provide new insights for future research.

Keywords: Circulating Tumor DNA; Gut Microbiome; Maintenance; Ovarian Cancer; PARP Inhibitor; Progression-Free Survival.

Grants and funding

JP23K06735/JSPS/Japan Society for the Promotion of Science/Japan