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

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.

[1]  Norikazu Masuda,et al.  Buparlisib plus fulvestrant versus placebo plus fulvestrant in postmenopausal, hormone receptor-positive, HER2-negative, advanced breast cancer (BELLE-2): a randomised, double-blind, placebo-controlled, phase 3 trial. , 2017, The Lancet. Oncology.

[2]  Xiao Han,et al.  Circulating Tumor DNA as Biomarkers for Cancer Detection , 2017, Genom. Proteom. Bioinform..

[3]  J. García-Saenz,et al.  Tumor burden monitoring using cell-free tumor DNA could be limited by tumor heterogeneity in advanced breast cancer and should be evaluated together with radiographic imaging , 2017, BMC Cancer.

[4]  A. Bardelli,et al.  Integrating liquid biopsies into the management of cancer , 2017, Nature Reviews Clinical Oncology.

[5]  Yi-xin Hao,et al.  Effectiveness of circulating tumor DNA for detection of KRAS gene mutations in colorectal cancer patients: a meta-analysis , 2017, OncoTargets and therapy.

[6]  Dexin Kong,et al.  Class I phosphatidylinositol 3-kinase inhibitors for cancer therapy , 2016, Acta pharmaceutica Sinica. B.

[7]  Niels Pallisgaard,et al.  Detecting Plasma Tumor DNA in Early-Stage Breast Cancer—Letter , 2015, Clinical Cancer Research.

[8]  I. Brandslund,et al.  Controls to validate plasma samples for cell free DNA quantification. , 2015, Clinica chimica acta; international journal of clinical chemistry.

[9]  S. Noguchi,et al.  PIK3CA mutations in serum DNA are predictive of recurrence in primary breast cancer patients , 2015, Breast Cancer Research and Treatment.

[10]  Carsten Denkert,et al.  Analysis of PIK3CA Mutations in Breast Cancer Subtypes , 2014, Applied immunohistochemistry & molecular morphology : AIMM.

[11]  F. Nicolantonio,et al.  Liquid biopsy: monitoring cancer-genetics in the blood , 2013, Nature Reviews Clinical Oncology.

[12]  Carlos Caldas,et al.  Analysis of circulating tumor DNA to monitor metastatic breast cancer. , 2013, The New England journal of medicine.

[13]  Johannes G. Reiter,et al.  The molecular evolution of acquired resistance to targeted EGFR blockade in colorectal cancers , 2012, Nature.

[14]  Ben H. Park,et al.  Detection of Tumor PIK3CA Status in Metastatic Breast Cancer Using Peripheral Blood , 2012, Clinical Cancer Research.

[15]  P. A. Futreal,et al.  Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. , 2012, The New England journal of medicine.

[16]  Niels Pallisgaard,et al.  Quantitative Cell-Free DNA, KRAS, and BRAF Mutations in Plasma from Patients with Metastatic Colorectal Cancer during Treatment with Cetuximab and Irinotecan , 2012, Clinical Cancer Research.

[17]  J. Barrett,et al.  PIK3CA Mutations May Be Discordant between Primary and Corresponding Metastatic Disease in Breast Cancer , 2010, Clinical Cancer Research.

[18]  M. Ranson,et al.  Detection of PIK3CA mutations in circulating free DNA in patients with breast cancer , 2010, Breast Cancer Research and Treatment.

[19]  W. Gerald,et al.  PIK3CA Mutation Associates with Improved Outcome in Breast Cancer , 2009, Clinical Cancer Research.

[20]  Zhi Hu,et al.  An integrative genomic and proteomic analysis of PIK3CA, PTEN, and AKT mutations in breast cancer. , 2008, Cancer research.

[21]  M. Monden,et al.  Clinicopathologic Analysis of Breast Cancers with PIK3CA Mutations in Japanese Women , 2007, Clinical Cancer Research.

[22]  B. Iacopetta,et al.  PIK3CA mutations in breast cancer are associated with poor outcome , 2006, Breast Cancer Research and Treatment.

[23]  A. Marchetti,et al.  PIK3CA mutation and histological type in breast carcinoma: high frequency of mutations in lobular carcinoma , 2006, The Journal of pathology.

[24]  B. Park,et al.  Mutation of the PIK3CA oncogene in human cancers , 2006, British Journal of Cancer.

[25]  Frank Diehl,et al.  Detection and quantification of mutations in the plasma of patients with colorectal tumors. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[26]  D. Pisetsky,et al.  The role of macrophages in the in vitro generation of extracellular DNA from apoptotic and necrotic cells , 2005, Immunology.

[27]  Hanina Hibshoosh,et al.  PIK3CA mutations correlate with hormone receptors, node metastasis, and ERBB2, and are mutually exclusive with PTEN loss in human breast carcinoma. , 2005, Cancer research.

[28]  Wayne A. Phillips,et al.  Mutation of the PIK3CA Gene in Ovarian and Breast Cancer , 2004, Cancer Research.

[29]  J. Jen,et al.  An Overview on the Isolation and Analysis of Circulating Tumor DNA in Plasma and Serum , 2000, Annals of the New York Academy of Sciences.

[30]  V. Vasioukhin,et al.  The Origin and Mechanism of Circulating DNA , 2000, Annals of the New York Academy of Sciences.

[31]  Steven J. M. Jones,et al.  Comprehensive molecular portraits of human breast tumours , 2013 .

[32]  L. Schwartz,et al.  New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). , 2009, European journal of cancer.