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Detection and Monitoring of Tumor Associated Circulating DNA in Patient Biofluids

Detection and Monitoring of Tumor Associated Circulating DNA in Patient Biofluids

Published on: June 8, 2019

PIK3CA mutations in plasma circulating tumor DNA predict survival and treatment outcomes in patients with advanced

E E Dumbrava¹, S G Call¹, H J Huang¹

¹Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, USA.

|September 3, 2021

Abstract

Background:

Oncogenic mutations in PIK3CA are prevalent in diverse cancers and can be targeted with inhibitors of the phosphoinositide-3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway. Analysis of circulating tumor DNA (ctDNA) provides a minimally invasive approach to detect clinically actionable PIK3CA mutations.

Patients And Methods:

We analyzed PIK3CA hotspot mutation frequency by droplet digital PCR (QX 200; BioRad) using 16 ng of unamplified plasma-derived cell-free DNA from 68 patients with advanced solid tumors (breast cancer, n = 41; colorectal cancer, n = 13; other tumor types, n = 14). Results quantified as variant allele frequencies (VAFs) were compared with previous testing of archival tumor tissue and with patient outcomes.

Results:

Of 68 patients, 58 (85%) had PIK3CA mutations in tumor tissue and 43 (74%) PIK3CA mutations in ctDNA with an overall concordance of 72% (49/68, κ = 0.38). In a subset analysis, which excluded samples from 26 patients known not to have disease progression at the time of sample collection, we found an overall concordance of 91% (38/42; κ = 0.74). PIK3CA-mutated ctDNA VAF of ≤8.5% (5% trimmed mean) showed a longer median survival compared with patients with a higher VAF (15.9 versus 9.4 months; 95% confidence interval 6.7-17.1 months; P = 0.014). Longitudinal analysis of ctDNA in 18 patients with serial plasma collections (range 2-22 time points, median 5) showed that those with a decrease in PIK3CA VAF had a longer time to treatment failure (TTF) compared with patients with an increase or no change (10.7 versus 2.6 months; P = 0.048).

Conclusions:

Detection of PIK3CA mutations in ctDNA is concordant with testing of archival tumor tissue. Low quantity of PIK3CA-mutant ctDNA is associated with longer survival and a decrease in PIK3CA-mutant ctDNA on therapy is associated with longer TTF.

Insights

Detecting PIK3CA mutations in circulating tumor DNA (ctDNA) shows high concordance with tumor tissue analysis. Lower levels of PIK3CA-mutant ctDNA correlate with improved survival and treatment response.

Area of Science:

Oncology
Molecular Diagnostics
Genetics

Background:

PIK3CA mutations are common drivers in many cancers.
The PI3K/AKT/mTOR pathway is a key target for cancer therapies.
Circulating tumor DNA (ctDNA) analysis offers a non-invasive method for detecting actionable mutations.

Purpose of the Study:

To evaluate the concordance of PIK3CA mutation detection in ctDNA versus tumor tissue.
To assess the prognostic value of ctDNA PIK3CA variant allele frequencies (VAFs) and their changes during treatment.

Main Methods:

Droplet digital PCR was used to analyze PIK3CA hotspot mutations in plasma-derived cell-free DNA from 68 patients with advanced solid tumors.
ctDNA results were compared with archival tumor tissue testing.
Patient outcomes, including survival and time to treatment failure (TTF), were correlated with ctDNA findings.

Main Results:

Overall concordance between ctDNA and tumor tissue PIK3CA mutation detection was 72%, increasing to 91% in a subset excluding patients without disease progression.
Lower ctDNA PIK3CA VAFs (≤8.5%) were associated with significantly longer median survival (15.9 vs. 9.4 months).
A decrease in ctDNA PIK3CA VAF during therapy correlated with longer TTF (10.7 vs. 2.6 months).

Conclusions:

ctDNA analysis is a reliable method for detecting PIK3CA mutations, showing good concordance with tissue-based testing.
ctDNA PIK3CA mutation levels and their dynamics during treatment are valuable prognostic biomarkers for advanced solid tumors.

Read full analysis

Keywords:

PIK3CA cancer circulating tumor DNA droplet digital PCR

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