The TIDE‐Cas14a system, an integrated RPA‐T7‐CRISPR/Cas14a cascade platform incorporating engineered crRNA mismatches, enables ultrasensitive detection of the PIK3CA H1047R mutation in breast cancer circulating tumor DNA, with a limit of detection as low as 0.01%, surpassing the sensitivity of droplet digital PCR. Here, PIK3CA is linked to breast carcinoma.