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. 2025 Oct 1;31(19):4122-4135.
doi: 10.1158/1078-0432.CCR-25-0512.

Surgical and Blood-Based Minimal Residual Disease in Patients with Ovarian Cancer after First-line Therapy: Clinical Outcomes and Translational Opportunities

Anne Knisely #  1 , Yibo Dai #  2   3 , Graham L Barlow #  4 , Sanghoon Lee  1 , Barrett Lawson  5 , Helen Clark  1 , Bryan Fellman  6 , Ying Yuan  6 , Wei Lu  7 , Idania Carolina Lubo Julio  7 , Rossana N Lazcano  5 , Manoj Chelvanambi  2   8 , Brenda Melendez  8 , Bharat Singh  8 , Bhavana Singh  7 , Khalida Wani  7 , Jianfeng Chen  9 , Chih-Chen Yeh  9 , Jianjun Gao  9 , Sean Barnes  7 , Ou Shi  7 , Khaja B Khan  7 , Alejandra G Serrano  7 , Lorena I Gomez-Bolanos  7 , Carly Bess Scalise  10 , Samantha K Cheung  10 , Punashi Dutta  10 , Sharlene Velichko  10 , Adam C ElNaggar  10 , Minetta C Liu  10 , Roni N Wilke  1 , Jeffrey How  1 , Lois M Ramondetta  1 , David M Boruta  1 , Gwyn Richardson  1 , Aaron Shafer  1 , Shannon N Westin  1 , Travis Sims  1 , Anil K Sood  1 , Pedro T Ramirez  11 , Alexander J Lazar  2   5   7 , Pamela T Soliman  1 , Karen Lu  12 , Cara L Haymaker  7 , Luisa M Solis Soto  7 , Jennifer A Wargo  2   8   13   14 , Rachel Grisham  15 , Kai W Wucherpfennig  4 , Linghua Wang  2   3   14   16 , Amir A Jazaeri  1
Affiliations

Surgical and Blood-Based Minimal Residual Disease in Patients with Ovarian Cancer after First-line Therapy: Clinical Outcomes and Translational Opportunities

Anne Knisely et al. Clin Cancer Res. .

Abstract

Purpose: Minimal residual disease (MRD) after first-line treatment of advanced-stage ovarian cancer remains a long-standing barrier to cure. We investigated the prognostic and translational value of MRD detection by second-look laparoscopy (SLL) and ctDNA at the completion of first-line therapy.

Experimental design: Patients with high-grade epithelial ovarian cancer who had a complete clinical response to first-line therapy and underwent SLL and plasma collection for ctDNA were included. Progression-free survival (PFS) and overall survival (OS) were estimated based on MRD and clinicopathologic status. Spatial transcriptomics (GeoMx and Visium) and proteomics (CODEX) profiling were performed on serial samples from select patients.

Results: Forty of 95 (42.1%) patients had surgically detected MRD, which was associated with worse PFS (median PFS 7.4 vs. 23.8 months; P < 0.001) and OS (median OS 33.9 vs. not reached; P < 0.001). SLL positivity was an independent negative prognostic factor for OS (HR, 4.40; 95% confidence interval, 1.37-14.21; P = 0.013) in multivariable analysis. Among 44 patients who underwent SLL and had ctDNA testing, 34% (15/44) were ctDNA-positive, which was associated with worse PFS (6.4 vs. 28.1 months; P < 0.001) and OS (32.4 months vs. not reached; P = 0.008). We demonstrated the feasibility of spatial multiomics in studying MRD and their ability to provide hypothesis-generating observations, implicating the upregulation of the hypoxia signaling pathway, expression of multiple druggable targets (CDK6, GLS, MSLN, ERBB2), and immune exclusion in MRD lesions.

Conclusions: Approximately half of patients in clinical remission after first-line therapy have assessable MRD, which can inform prognosis, therapeutic target discovery, and clinical trials.

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Conflict of interest statement

Y. Yuan reports other support from Polaris Consulting LLC outside the submitted work. C.B. Scalise reports other support from Natera, Inc., outside the submitted work. P. Dutta reports other support from Natera, Inc. outside the submitted work. A.C. ElNaggar reports employment with Natera, Inc., and ownership or potential ownership of Natera, Inc., stock. M.C. Liu reports other support from Natera, Inc., outside the submitted work. S.N. Westin reports grants and personal fees from AstraZeneca, Bayer, Clovis Oncology/Pharm&, Daiichi Sankyo, GSK, Loxo, Mereo, Nuvectis, Pfizer, Roche/Genentech, Verastem, and Zentalis; grants from AvengeBio, Bio-Path, Jazz Pharmaceuticals, and Novartis; and personal fees from Caris, Corcept, Eisai, Gilead, Immunocore, ImmunoGen, Incyte, Lilly, Merck, Mersana, NGM Bio, SeaGen, and ZielBio outside the submitted work. A.K. Sood reports grants from the NCI, American Cancer Society, and Pfizer; personal fees from Iylon and from Onxeo; and other support from Advenchen and Mural Oncology outside the submitted work. C.L. Haymaker reports grants from the NIH during the conduct of the study as well as grants from Sanofi, Avenge, Iovance, KSQ Therapeutics, Theolytics, BTG, Novartis, 280Bio, AstraZeneca, EMD Serono, Takeda, Obsidian, Genentech, Bristol Myers Squibb, Summit Therapeutics, Artidis, and Immunogenesis; personal fees from Regeneron; and other support from Briacell outside the submitted work. L.M. Solis Soto reports other support from Theolytics and 10× Genomics and personal fees from BioNTech outside the submitted work. R. Grisham reports grants from Break Through Cancer during the conduct of the study as well as personal fees from AstraZeneca, Incyte, Physician Education Resources, MJH Health, Genmab, and Curio and nonfinancial support from Verastem outside the submitted work; in addition, R. Grisham has a patent for avutometinib and defactinib for mesonephric cancer pending. K.W. Wucherpfennig reports personal fees and other support from DEM BioPharma, Solu Therapeutics, D2M Biotherapeutics, DoriNano Inc., Immunitas Therapeutics, and TScan Therapeutics and personal fees from Nextechinvest outside the submitted work. L. Wang serves as a member of the Scientific Advisory Board for SELLAS Life Sciences and receives compensation outside the scope of this submitted work. A.A. Jazaeri reports nonfinancial support and other support from Natera and grants from Break Through Cancer during the conduct of the study as well as nonfinancial support from Personalis, Saga, and Imunon and other support from Merck outside the submitted work. No disclosures were reported by the other authors.

Figures

Figure 1.
Figure 1.
Clinical study design and prognostic significance of MRD in high-grade serous ovarian cancer. A, Clinical study design. A total of 95 patients who received standard upfront treatment and were in complete clinical remission underwent SLL, among whom 44 also underwent ctDNA testing. B and C, PFS (B) and OS (C) in patients with distinct sMRD status. D and E, PFS (D) and OS (E) in patients with distinct MRD status as determined by ctDNA testing. F, PFS of patients based on SLL and ctDNA detection of MRD. (A, Created with BioRender.com. Dai, Y. https://BioRender.com/0894jqk.)
Figure 2.
Figure 2.
Translational study design and characteristics of cancer cells in MRD lesions. A, Translational study design. A pilot cohort of four MRD+ and three MRD− cases was studied, with samples collected at three different time points along the treatment course. These samples underwent spatial profiling using GeoMx DSP, Visium, and CODEX on adjacent tissue sections. B, Clinical course and sampling time points for a representative case, Pt-10. C, Histopathologic features of the MRD sample (sample 3A) from Pt-10, revealing microscopic tumor lesions with adjacent vascular invasion. D–F, Spatial profiling of the MRD sample (3A) using three different platforms. Tumor regions were consistently identified across all three platforms and exhibited proliferative activity. G, GeoMx data showing significant enrichment of the hypoxia signaling pathway in MRD tumors compared with IDS tumors. The comparison includes all SLL and IDS samples from the pilot cohort. H, Visium data showing hypoxia-related genes highly expressed in the tumor region of sample 3A. I, CODEX data showing CA9 protein expression in the tumor region of the same sample. J, Progressive upregulation of ABC family transporter genes in MRD-positive cases. The comparison is based on tumor compartments across all MRD+ cases in the pilot cohort. P values were calculated with one-way ANOVA and adjusted using the Benjamini–Hochberg method. K, Visium data showing ABC family transporter genes highly expressed in the tumor region of sample 3A. MSigDB, Molecular Signature Database (A, Created with BioRender.com. Dai, Y. https://BioRender.com/v5rzzoi.)
Figure 3.
Figure 3.
Immune exclusion in SLL sample 1B revealed by orthogonal spatial profiling. A, CODEX profiling identified two representative regions in the MRD sample 1B of Pt-19 with distinct tumor phenotypes and TME spatial features. CD8+ T cells were intermixed with tumor islands in region 1, whereas in region 2, they were confined to the peritumoral stromal area. B, Visium spatial profiling of the same sample as in A. In the central area of the sample, CD8+ T-cell signals were detected surrounding but excluded from the tumor core, overlapping with signals from immune checkpoint genes, CAF markers, and IFN-stimulated genes. C, GeoMx profiling of an adjacent section identified two regions of interest with similar spatial locations as in A, with the two regions showing distinct expression levels of IFN-stimulated genes.
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