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

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.

Informations de copyright

Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.

Déclaration de conflit d'intérêts

Disclosure FJ has research support from Novartis, Genentech, BioMed Valley Discoveries, Astellas, Agios, Plexxikon, Deciphera, PIQUR, Symphogen, Bristol-Myers Squibb, Asana, and Upsher-Smith Laboratories; is or has been on the Scientific Advisory Boards of Guardant Health, IFM Therapeutics, Synlogic, and Deciphera; is a paid consultant for Cardiff Oncology and ImmunoMet; and has ownership interests in Cardiff Oncology. MF reports grants and personal consulting fees through 06/04/18 from Seattle Genetics and salary and stocks from 10/01/18 following the start of her employment with Seattle Genetics; grants and personal fees from Takeda, Celgene, BMS, and Merck through 06/04/18; grants from ADC Therapeutics, Molecular Templates, MedImmune, Gilead, and Genentech through 06/04/18; and personal fees from Bayer and Spectrum through 06/04/18. VS has research funding/grant support for clinical trials (to institution) from Novartis, Bayer, Berghealth, Incyte, Fujifilm, PharmaMar, D3, Pfizer, MultiVir, Amgen, AbbVie, Alfa-sigma, Agensys, Boston Biomedical, Idera Pharma, Inhibrx, Exelixis, Blueprint Medicines, Loxo Oncology, MedImmune, Altum, Dragonfly Therapeutics, Takeda and, National Comprehensive Cancer Network, NCI-CTEP, UT MD Anderson Cancer Center, Turning point therapeutics, and Boston Pharmaceuticals; travel funding from Novartis, PharmaMar, ASCO, ESMO, Helsinn, Incyte; and serves on the advisory board of Helsinn, LOXO Oncology/ Eli Lilly, R-Pharma US, INCYTE, QED pharma, Astra-Zeneca/Medimmune, Novartis, Signant Health. The remaining authors have declared no conflicts of interest.