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. 2025 May;36(3):e38.
doi: 10.3802/jgo.2025.36.e38. Epub 2024 Oct 21.

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

Mika Okazawa-Sakai #  1   2 , Shunsuke A Sakai #  3   4 , Ichinosuke Hyodo  5 , Satoshi Horasawa  6 , Kentaro Sawada  7 , Takao Fujisawa  6   8 , Yasuko Yamamoto  9 , Shogen Boku  10 , Yoh Hayasaki  11 , Masanori Isobe  11 , Daisuke Shintani  12 , Kosei Hasegawa  12 , Tomomi Egawa-Takata  13 , Kimihiko Ito  13 , Kei Ihira  14 , Hidemichi Watari  14 , Kazuhiro Takehara  1 , Hiroshi Yagi  15 , Kiyoko Kato  15 , Tatsuyuki Chiyoda  16 , Kenichi Harano  17 , Yoshiaki Nakamura  6   18   19 , Riu Yamashita  4   20 , Takayuki Yoshino  19 , Daisuke Aoki  16   21
Affiliations

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

Mika Okazawa-Sakai et al. J Gynecol Oncol. 2025 May.

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.

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Conflict of interest statement

Mika Okazawa-Sakai declares no competing interests. Shunsuke A. Sakai declares no competing interests. Ichinosuke Hyodo reports advisory roles for Asahi-Kasei, Ono, Taiho, Chugai, and Eisai Pharmaceutical Companies. Satoshi Horasawa declares no competing interests. Kentaro Sawada declares no competing interests. Takao Fujisawa reports honoraria from Amelieff Co. Ltd. Yasuko Yamamoto declares no competing interests. Shogen Boku reports honoraria from Nippon Kayaku Co., Ltd., Chugai Pharmaceutical Co., Ltd., Taiho Pharmaceutical Co., Ltd., Bristol-Myers Squibb Japan, and MSD. Yoh Hayasaki declares no competing interests. Masanori Isobe declares no competing interests. Daisuke Shintani declares no competing interests. Kosei Hasegawa reports honoraria from AstraZeneca, GSK, MSD, and Takeda; advisory role for GSK, MSD, and Takeda; research grants from MSD. Tomomi Egawa-Takata declares no competing interests. Kimihiko Ito reports honoraria from AstraZeneca. Kei Ihira declares no competing interests. Hidemichi Watari reports honoraria from AstraZeneca, Takeda, MSD, and Chugai. Kazuhiro Takehara reports honoraria from AstraZeneca, Takeda, MSD, Chugai, Eisai, and Sanofi. Hiroshi Yagi declares no competing interests. Kiyoko Kato declares no competing interests. Tatsuyuki Chiyoda reports research grants from Takeda Pharmaceutical Company. Kenichi Harano reports honoraria from AstraZeneca, Chugai, Eizai, MSD, Taiho and Takeda, and advisory roles for AstraZeneca, Chugai, Eizai, Taiho and Takeda. Yoshiaki Nakamura declares advisory role from Guardant Health Pte Ltd., Natera, Inc., Roche Ltd., Seagen, Inc., Premo Partners, Inc., Daiichi Sankyo Co., Ltd., Takeda Pharmaceutical Co., Ltd., Exact Sciences Corporation, Gilead Sciences, Inc.; speakers' bureau from Guardant Health Pte Ltd., MSD K.K., Eisai Co., Ltd., Zeria Pharmaceutical Co., Ltd., Miyarisan Pharmaceutical Co., Ltd., Merck Biopharma Co., Ltd., CareNet, Inc., Hisamitsu Pharmaceutical Co., Inc., Taiho Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Chugai Pharmaceutical Co., Ltd., Becton, Dickinson and Company, Guardant Health Japan Corp; research funding from Seagen, Inc., Genomedia Inc., Guardant Health AMEA, Inc., Guardant Health, Inc., Tempus Labs, Inc., Roche Diagnostics K.K., Daiichi Sankyo Co., Ltd., Chugai Pharmaceutical Co., Ltd. Riu Yamashita declares no competing interests. Takayuki Yoshino reports honoraria from Chugai Pharma, Takeda Pharma, Merck, Bayer Yakuhin, Ono Pharmaceutical and MSD K. K.; consulting fees from Sumitomo Corp.; and research grants from Amgen, Bristol-Myers Squibb, Chugai, Daiichi Sankyo, Eisai, FALCO Biosystems, Genomedia Inc., Medical & Biological Laboratories, Merus N.V., Molecular Health, MSD, Nippon Boehringer Ingelheim, Ono, Pfizer, Roche Diagnostics, Sanofi, Sysmex, Taiho and Takeda. Daisuke Aoki reports honoraria from AstraZeneca, Takeda, MSD, Chugai, and Myriad Genetics.

Figures

Fig. 1
Fig. 1. Patients and samples. (A) Patients. Among 110 patients with ovarian cancer enrolled in the MONSTAR-SCREEN study, 56 patients who underwent PARPi maintenance therapy after the response to platinum-based chemotherapy and provided baseline blood and fecal samples were analyzed. (B) Samples. Baseline samples were collected before or immediately after the start of PARPi treatment. Last samples were collected at PD or the last follow-up during the period from December 2021 to January 2022.
PARPi, poly(ADP-ribose) polymerase inhibitor; PD, progressive disease.
Fig. 2
Fig. 2. Landscape of gut microbiome based on BRCA1/2mut status. (A) Violin plot of the number of amplicon sequence variants to compare taxonomic richness (alpha diversity). (B) PCoA plot (beta diversity). (C) Phylum-level microbial composition. (D) LEfSe representation of microbial relative abundance comparing between patients with and without BRCA1/2mut.
ASVs, amplicon sequence variants; BRCA1/2mut, BRCA1/2 mutation; f, family; g, genus; LDA, linear discriminant analysis; LEfSe, linear discriminant analysis of effect size; PCoA, principal coordinate analysis; PERMANOVA, permutation multivariate analysis of variance.
Fig. 3
Fig. 3. Microbial compositions and PFS. LEfSe representation of microbial relative abundance between LTR (green) and STR (red) in fecal baseline samples of (A) patients with BRCA1/2mut and (B) patients without BRCA1/2mut. Multivariate analyses of enriched bacteria for PFS in (C) patients with BRCA1/2mut and (D) patients without BRCA1/2mut.
BRCA1/2mut, BRCA1/2 mutation; c, class; CI, confidence interval; f, family; g, genus; HR, hazard ratio; LDA, linear discriminant analysis; LEfSe, linear discriminant analysis of effect size; LTR, long-term responder; o, order; p, phylum; PFS, progression-free survival; STR, short-term responder.
Fig. 4
Fig. 4. Kaplan–Meier estimate plots of PFS according to relative abundances of Phascolarctobacterium in patients without BRCA1/2mut.
BRCA1/2mut, BRCA1/2 mutation; CI, confidence interval; HR, hazard ratio; NE, not estimable; PFS, progression-free survival.
Fig. 5
Fig. 5. Paired-sample analysis for gut microbes in patients without BRCA1/2 mutations. (A) Changes in relative abundances between baseline and last samples of patients without PD (n=5) and with PD (n=15). Red dotted lines indicate the median value of relative abundances in baseline samples used in the multivariate analyses. (B) Boxplots for the relative abundances in the samples at the last follow-up without PD (n=5) and at PD (n=15).
PARPi, poly(ADP-ribose) polymerase inhibitor; PD, progressive disease.
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