As reported in the Nov. 5, 2020 issue of JAMA Oncology, as many as half of all liquid biopsy-identified DDR (DNA Damage Response) mutations may be false positives. This may lead to patients being treated inappropriately with PARP inhibitors such as Olaparib or Rucaparib.
The cause of these false positives is what are known as CHIP variants. CHIP is an acronym for Clonal Hematopoiesis of Indeterminate Potential. These are clonal mutations of Stem cells of blood forming organs, primarily the bone marrow. This is a mostly harmless phenomenon that occurs with increasing frequency as we age. Some of these CHIP variants include the same mutations found in advanced and metastatic prostate cancer patients, but the CHIP variants are not related to prostate cancer at all.
The most common DDR CHIP variant the authors identified was ATM, followed by BRCA2 and CHEK2. The authors speculate that these false ATM mutations may account for the low response rates of prostate cancer patients treated with Olaparib.
Most commercial testing labs use only plasma samples for liquid biopsies called cfDNA testing, i.e., cell-free DNA. The authors found that CHIP interference variants could be distinguished from prostate cancer variants using a paired whole-blood control along with the plasma specimen. Sorry, I know this is kinda technical. But the bottom line is this: If you get a liquid biopsy and they are sequencing cfDNA to detect prostate cancer mutations, ask them if they use a whole-blood control along with the plasma specimen.
The full article can be read here:
https://jamanetwork.com/journals/jamaoncology/fullarticle/2772786
The Medscape summary of the article can be read here: