Correlation between circulating cell-free PIK3CA tumor DNA levels and treatment response in patients with PIK3CA-mutated metastatic breast cancer.

Annette R Kodahl,Niels Pallisgaard,Anne‐Vibeke Lænkholm,Henrik J Ditzel,Sidse Ehmsen,Anne M B Jylling,Ann S Knoop,Jeanette D Jensen,Anne-Vibeke Laenkholm

doi:10.1002/1878-0261.12305

Abstract

Liquid biopsies focusing on the analysis of cell‐free circulating tumor DNA (ctDNA) may have important clinical implications for personalized medicine, including early detection of cancer, therapeutic guidance, and monitoring of recurrence. Mutations in the oncogene, PIK3CA, are frequently observed in breast cancer and have been suggested as a predictive biomarker for PI3K‐selective inhibitor treatment. In this study, we analyzed the presence of PIK3CA mutations in formalin‐fixed, paraffin‐embedded, metastatic tissue and corresponding ctDNA from serum of patients with advanced breast cancer using a highly sensitive, optimized droplet digital PCR (ddPCR) assay. We found 83% of patients with PIK3CA mutation in the metastatic tumor tissue also had detectable PIK3CA mutations in serum ctDNA. Patients lacking the PIK3CA mutation in corresponding serum ctDNA all had nonvisceral metastatic disease. Four patients with detectable PIK3CA‐mutated ctDNA were followed with an additional serum sample during oncological treatment. In all cases, changes in PIK3CA ctDNA level correlated with treatment response. Our results showed high concordance between detection of PIK3CA mutations in tumor tissue and in corresponding serum ctDNA and suggest that serum samples from patients with advanced breast cancer and ddPCR may be used for PIK3CA mutation status assessment to complement imaging techniques as an early marker of treatment response.

Highlights

Cell-free DNA is released from both normal and cancer cells into the circulation (Choi et al, 2005; Stroun et al, 2000)
This study aimed to investigate whether PIK3CA mutations identified in archived formalin-fixed, paraffin-embedded (FFPE), metastatic tissue samples of breast cancer patients could be detected in their corresponding circulating tumor DNA (ctDNA) from serum samples using an optimized droplet digital PCR assay (Kodahl et al, 2015)
Archived formalin-fixed, paraffin-embedded metastatic tumor biopsies and corresponding serum samples were available from 66 patients with metastatic disease who were part of a prospective study (2007–2013) at the Department of Oncology, Odense University Hospital, Denmark (Fig. 2)

Summary

Introduction

Cell-free DNA is released from both normal and cancer cells into the circulation (Choi et al, 2005; Stroun et al, 2000). In contrast to benign tumors and other noncancerous conditions, a rapid turnover of tumor cells is thought to result in a consistently increased release of circulating tumor DNA (ctDNA; Diehl et al, 2005). This enables clinical use of repeated and noninvasive blood samples as a ‘liquid biopsy’ to monitor the dynamic evolution of human cancers (Siravegna et al, 2017) and response to treatment, which could accompany the well-established RECIST 1.1 and PERCIST 1.0 criteria evaluative of changes in tumor burden during cancer treatment (Eisenhauer et al, 2009). Additional PI3K inhibitors are currently under clinical development (Zhao et al, 2017)

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