Prospective Longitudinal ctDNA Workflow Reveals Clinically Actionable Alterations in Ovarian Cancer.

Abstract

PURPOSE:

Circulating tumor DNA (ctDNA) detection is a minimally invasive technique that offers dynamic molecular snapshots of genomic alterations in cancer. Although ctDNA markers can be used for early detection of cancers or for monitoring treatment efficacy, the value of ctDNA in guiding treatment decisions in solid cancers is controversial. Here, we monitored ctDNA to detect clinically actionable alterations during treatment of high-grade serous ovarian cancer, the most common and aggressive form of epithelial ovarian cancer with a 5-year survival rate of 43%.

PATIENTS AND METHODS:

We implemented a clinical ctDNA workflow to detect clinically actionable alterations in more than 500 cancer-related genes. We applied the workflow to a prospective cohort consisting of 78 ctDNA samples from 12 patients with high-grade serous ovarian cancer before, during, and after treatment. These longitudinal data sets were analyzed using our open-access ctDNA-tailored bioinformatics analysis pipeline and in-house Translational Oncology Knowledgebase to detect clinically actionable genomic alterations. The alterations were ranked according to the European Society for Medical Oncology scale for clinical actionability of molecular targets.

RESULTS:

Our results show good concordance of mutations and copy number alterations in ctDNA and tumor samples, and alterations associated with clinically available drugs were detected in seven patients (58%). Treatment of one chemoresistant patient was changed on the basis of detection of ERBB2 amplification, and this ctDNA-guided decision was followed by significant tumor shrinkage and complete normalization of the cancer antigen 125 tumor marker.

CONCLUSION:

Our results demonstrate a proof of concept for using ctDNA to guide clinical decisions. Furthermore, our results show that longitudinal ctDNA samples can be used to identify poor-responding patients after first cycles of chemotherapy. We provide what we believe to be the first comprehensive, open-source ctDNA workflow for detecting clinically actionable alterations in solid cancers.

• Authors: Jaana Oikkonen, Kaiyang Zhang, Liina Salminen, Ingrid Schulman, Kari Lavikka, Noora Andersson, Erika Ojanperä, Sakari Hietanen, Seija Grénman, Rainer Lehtonen, Kaisa Huhtinen, Olli Carpén, Johanna Hynninen, Anniina Färkkilä, Sampsa Hautaniemi
• Journal: JCO precision oncology (JCO Precis Oncol) Vol. 3 ( 2019) ISSN: 2473-4284 [Electronic] United States
• PMID: 32914024 (Publication Type: Journal Article)
• Copyright: © 2019 by American Society of Clinical Oncology.