National clinical study

Værdien af cirkulerende tumor DNA og patient rapporterede outcomes til tidlig recidivopsporing hos kvinder med vulva cancer - The Danish Vulva Cancer Recurrence Study (DaVulvaRec)

VC is a rare disease often diagnosed in elderly and comorbid women. It comes with an HPV associated and an HPV independent aetiology; the latter is more common and carries the worst prognosis. Treatment of VC is surgically mutilating, and adjuvant or primary chemo-radiation add further to complications and late effects. Up to 40% of the patients experience at least one recurrence. Despite intensive clinical follow-up programs, VC recurrence is often detected late and knowledge regarding symptomatology preceding a clinical recurrence is limited. No imaging modality has proven valuable in the follow-up setting. Hence, there is an urgent need to identify new biomarkers and diff erent clinical strategies for future personalized surveillance programs for VC patients.

Abstract

Perspectives: Treatment and postoperative surveillance programs for vulva cancer (VC) currently rely on a “one size fi ts all” concept with inguinal lymph node metastases as the only clinical biomarker available. Circulating tumor DNA (ctDNA) may represent a novel technological advancement for individualized treatment allocation and risk-stratified postoperative recurrence detection. Systematic assessment and pro-active intervention based on patient reported outcome measures (PROMs) may supplement early recurrence detection.

Identification and implementation of a suitable ctDNA panel along with a patient directed PROM-based approach focusing on alarm symptoms will improve future treatment allocation and surveillance programs and is likely to improve survival.

Background: VC is a rare disease often diagnosed in elderly and comorbid women. It comes with an HPV associated and an HPV independent aetiology; the latter is more common and carries the worst prognosis. Treatment of VC is surgically mutilating, and adjuvant or primary chemo-radiation add further to complications and late effects. Up to 40% of the patients experience at least one recurrence. Despite intensive clinical follow-up programs, VC recurrence is often detected late and knowledge regarding symptomatology preceding a clinical recurrence is limited. No imaging modality has proven valuable in the follow-up setting. Hence, there is an urgent need to identify new biomarkers and diff erent clinical strategies for future personalized surveillance programs for VC patients.

Aim: To identify clinically relevant ctDNA in VC and to investigate if ctDNA in plasma samples predict disease stage besides persistent and recurrent disease after treatment with curative intent and during post-treatment surveillance.

Further, to investigate if systematic algorithm-based intervention on PROM assessment during surveillance may enhance early clinical recurrence detection.

Methods: All patients with primary or recurrent VC are eligible and are included from all five regions in Denmark. We will collect liquid biopsies to identify ctDNA in women with VC at the time of diagnosis, 2-4 weeks after treatment, and prospectively every 4 months up to two years after treatment. Further, we will collect and analyze algorithm-based PROM data at the time of diagnosis andduring surveillance to evaluate symptomatology which may trigger a time-accelerated clinical check-up and a liquid biopsy due to suspected recurrence. If recurrence is detected, the patient undergoes a PET CT-scan.

We will perform a proof-of concept study on the first 75 patients included using two different strategies: ddPCR assays for analyses of HPV positive cases to evaluate HPV specific genes (i.e. E6 and E7) and targeted ctDNA analyses in HPV negative cases. Exome sequencing of tumor DNA will be performed in tissue samples and in reference liquid biopsies to identify the most common mutations in VC. These results are used to design a patient specific next-generation-sequencing (NGS) assay with the most common mutated genes identified in this patient cohort to determine the value of ctDNA analysis. Tumor informed analysis is needed to obtain the highest sensitivity and specificity, which is needed to determine clinical value. This panel strategy is developed and used at MOMA routinely.

Following the proof-of-concept study we will determine the best way forward for further analyses, e.g., expanded panel, or supplement with droplet digital PCR assays. The NGS-panel strategy will be used for ctDNA analyses of liquid biopsies at diagnosis, after treatment and during surveillance on the first 75 patients included. Results of the ctDNA analyses are correlated to information on stage, disease distribution, and recurrence detection during surveillance. To evaluate the prognostic and predictive power of ctDNA, we will continue to collect liquid biopsies prospectively in a larger cohort of 295 patients for future large-scale testing and refining.

Patient enrolment started ultimo August 2024 at AUH and is expanded to RH on January 1st, 2025. All eligible AUH patients have been included in the study (7 patients). In Denmark, 120 patients are diagnosed with VC every year, and 25-40% of patients with prior VC are diagnosed with recurrence and are eligible. We expect to include the first 75 patients during 2025 and to finalize the analyses in the proof-of-concept study November 2025.

Expected outcomes: We expect the proof-of-concept study will pave the way for the development of a ctDNA test strategy which can be expanded in future ctDNA based studies. Ideally, a single NGS panel can be developed that can be sued to identify ctDNA in most VC patients based on the most VC-specific and common mutations identified by exome sequencing in this patient cohort and based on literature studies.

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