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Translational Therapeutics

Tumour microenvironment characterisation to stratify patients for hyperthermic intraperitoneal chemotherapy in high-grade serous ovarian cancer (OVHIPEC-1)

Abstract

Background

Hyperthermic intraperitoneal chemotherapy (HIPEC) improves survival in patients with Stage III ovarian cancer following interval cytoreductive surgery (CRS). Optimising patient selection is essential to maximise treatment efficacy and avoid overtreatment. This study aimed to identify biomarkers that predict HIPEC benefit by analysing gene signatures and cellular composition of tumours from participants in the OVHIPEC-1 trial.

Methods

Whole-transcriptome RNA sequencing data were retrieved from high-grade serous ovarian cancer (HGSOC) samples from 147 patients obtained during interval CRS. We performed differential gene expression analysis and applied deconvolution methods to estimate cell-type proportions in bulk mRNA data, validated by histological assessment. We tested the interaction between treatment and potential predictors on progression-free survival using Cox proportional hazards models.

Results

While differential gene expression analysis did not yield any predictive biomarkers, the cellular composition, as characterised by deconvolution, indicated that the absence of macrophages and the presence of B cells in the tumour microenvironment are potential predictors of HIPEC benefit. The histological assessment confirmed the predictive value of macrophage absence.

Conclusion

Immune cell composition, in particular macrophages absence, may predict response to HIPEC in HGSOC and these hypothesis-generating findings warrant further investigation.

Clinical trial registration

NCT00426257.

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Fig. 1: CONSORT diagram of OVHIPEC-1 participants and tissue availability.
Fig. 2: Summary of methods diagram.
Fig. 3: Bulk differential gene expression analysis.
Fig. 4: Deconvolution of bulk RNA sequencing data to estimate cell-type abundance using single-cell expression reference profiles.
Fig. 5: Predictive delta treatment score based on single-cell deconvolution.
Fig. 6: Forest plot of exploratory subgroup analysis for overall survival based on histopathological assessment.

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Data availability

Single-cell sequences for constructing reference profiles for deconvolution are publicly available [35], as well as count matrix and deconvolution results. The code used in generating the results is made available on https://github.com/cwlkr/DTSIC_HIPEC. Clinical data and RNA-seq data supporting this work are available upon reasonable request. Requests to access data should be made to the Netherlands Cancer Institute’s scientific repository at repository@nki.nl, which will contact the corresponding author. The institutional review board of the Netherlands Cancer Institute will review all requests.

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Acknowledgements

The authors thank all patients and their families and caregivers for participating in the present study. We thank the Core Facility of Molecular Pathology and Biobanking, S Cornelissen and D Peters for their support in processing of the samples; RJC Kluin, W Brugman, and the Genomics Core Facility for their support with sequencing; the principal investigators of the participating sites in patient recruitment and sample acquisition. The present study was funded by the Dutch National Cancer Foundation (KWF) and sponsored by the NKI. The funding sources had no role in the design and execution of the study, data analysis or writing of the manuscript.

Funding

The OVHIPEC-1 trial was funded by the Dutch Cancer Foundation (KWF Kankerbestrijding; NKI 2006–4176, to WJvD). Further financial support came from the Department of Defense Ovarian Cancer Research Program (Award No. W81XWH-22-1-0557), the Swiss National Science Foundation (320030M_219453), the Swiss Cancer League (KFS-5519-02-2022), and the ISREC Foundation (to SR). JvR received funding from the Josef Steiner Cancer Research Foundation.

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Contributions

KH, LvK, JvR, SR, WJvD, GSS, SNK and CARL were involved in the conceptualisation. WJvD was the coordinating principal investigator for the clinical study and was responsible for funding acquisition. SR, JvR and GSS were also responsible for funding acquisition. SLA, SNK, GSS and WJvD were involved in clinical data collection. KKvdV, JS and HMH performed manual pathology scoring. MA performed the processing of the tissue samples. SLA performed the histopathological analysis under the supervision of MLY. CW performed the deconvolution analyses under the supervision of LvK, KH and SR. BT performed the gene expression analyses. SLA, CW, BT, KH and LvK, interpreted the data. SLA, CW, BT and KH wrote the original draft of the manuscript. KH, LvK, JvR, SR, WJvD and GSS supervised the study. All authors were involved in critically revising the report. All authors approved the final version and took responsibility for the decision to submit the manuscript for publication.

Corresponding author

Correspondence to Willemien J. van Driel.

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Competing interests

KKVdV has served on advisory boards for Exact Sciences and AstraZeneca. HMH received honoraria from Roche Diagnostics BV. GSS has received institutional research support from Merck Sharp & Dohme, Agendia, AstraZeneca, Roche, and Novartis, and consulting fees from Biovica and Seagen. KH is a former employee at the Netherlands Cancer Institute and is currently working for Roche, Pharmaceutical Sciences, Basel, Switzerland. The research for this project was conducted in her position of researcher at the NKI. The remaining authors declare no competing interests.

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The protocol was approved by the local ethics committee at each of the participating centres. All patients provided written informed consent prior to enrolment. This study was performed in accordance with the Declaration of Helsinki.

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Aronson, S.L., Walker, C., Thijssen, B. et al. Tumour microenvironment characterisation to stratify patients for hyperthermic intraperitoneal chemotherapy in high-grade serous ovarian cancer (OVHIPEC-1). Br J Cancer (2024). https://doi.org/10.1038/s41416-024-02731-6

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